Heterocyclic aspartyl protease inhibitors

ABSTRACT

Disclosed are compounds of the formula I 
                         
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein
         W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—;   X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—;   U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond;   and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I.       
     Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. 
     Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1  agonist or m 2  antagonist.

FIELD OF THE INVENTION

This invention relates to heterocyclic aspartyl protease inhibitors,pharmaceutical compositions comprising said compounds, their use in thetreatment of cardiovascular diseases, cognitive and neurodegenerativediseases, and their use as inhibitors of the Human ImmunodeficiencyVirus, plasmepsins, cathepsin D and protozoal enzymes.

BACKGROUND

Eight human aspartic proteases of the A1 (pepsin-like) family are knownto date: pepsin A and C, renin, BACE, BACE 2, Napsin A, cathepsin D inpathological conditions.

The role of renin-angiotensin system (RAS) in regulation of bloodpressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 291:381-401/446-57). The octapeptideAngiotensin-II, a potent vasoconstrictor and stimulator for release ofadrenal aldosterone, was processed from the precursor decapeptideAngiotensin-I, which in turn was processed from angiotensinogen by therenin enzyme. Angiotensin-II was also found to play roles in vascularsmooth muscle cell growth, inflammation, reactive oxygen speciesgeneration and thrombosis, influence atherogenesis and vascular damage.Clinically, the benefit of interruption of the generation ofangiotensin-II through antagonism of conversion of angiotensin-I hasbeen well known and there are a number of ACE inhibitor drugs on themarket. The blockade of the earlier conversion of angiotensinogen toangiotensin-I, i.e. the inhibition of renin enzyme, is expected to havesimilar but not identical effects. Since renin is an aspartyl proteasewhose only natural substrate is angiotensinogen, it is believed thatthere would be less frequent adverse effect for controlling high bloodpressure and related symptoms regulated by angiotensin-II through itsinhibition.

Another protease, Cathepsin-D, is involved in lysosomal biogenesis andprotein targeting, and may also be involved in antigen processing andpresentation of peptide fragments. It has been linked to numerousdiseases including, Alzheimer's, disease, connective tissue disease,muscular dystrophy and breast cancer.

Alzheimer's disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase activity responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result β-secretase activity,inhibition of BACE-1 should inhibit formation of Aβ peptides. Thusinhibition of BACE-1 is a therapeutic approach to the treatment of ADand other cognitive and neurodegenerative diseases caused by Aβ plaquedeposition.

Human immunodeficiency virus (HIV), is the causative agent of acquiredimmune deficiency syndrome (AIDS). It has been clinically demonstratedthat compounds such as indinavir, ritonavir and saquinavir which areinhibitors of the HIV aspartyl protease result in lowering of viralload. As such, the compounds described herein would be expected to beuseful for the treatment of AIDS. Traditionally, a major target forresearchers has been HIV-1 protease, an aspartyl protease related torenin.

In addition, Human T-cell leukemia virus type I (HTLV-I) is a humanretrovirus that has been clinically associated with adult T-cellleukemia and other chronic diseases. Like other retroviruses, HTLV-Irequires an aspartyl protease to process viral precursor proteins, whichproduce mature virions. This makes the protease an attractive target forinhibitor design. (Moore, et al. Purification of HTLV-I Protease andSynthesis of Inhibitors for the treatment of HTLV-I Infection 55^(th)Southeast Regional Meeting of the American Chemical Society, Atlanta,Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN2004:137641 CAPLUS.)

Plasmepsins are essential aspartyl protease enzymes of the malarialparasite. Compounds for the inhibition of aspartyl proteasesplasmepsins, particularly I, II, IV and HAP, are in development for thetreatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, etal. Aspartic proteases of Plasmodium vivax are highly conserved in wildisolates Korean Journal of Prasitology (2004 June), 42(2) 61-6. Journalcode: 9435800) Furthermore, compounds used to target aspartyl proteasesplasmepsins (e.g. I, II, IV and HAP), have been used to kill malarialparasites, thus treating patients thus afflicted.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a stereoisomer, tautomer, or pharmaceutically acceptable salt,solvate or ester thereof, wherein

W is a bond, —C(═S)—, —S(O)—, —S(O)₂—, —C(═O)—, —O—, —C(R⁶)(R⁷)—,—N(R¹⁵)— or —C(═N(R⁵))—;

X is —O—, —N(R⁵)— or —C(R⁶)(R⁷)—; provided that when X is —O—, U is not—O—, —S(O)—, —S(O)₂—, —C(═O)— or —C(═NR⁵)—;

U is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —P(O)(OR¹⁵)—, —C(═NR⁵)—,—(C(R⁶)(R⁷))_(b)— or —N(R⁵)—; wherein b is 1 or 2; provided that when Wis —S(O)—, —S(O)₂—, —O—, or —N(R⁵)—, U is not —S(O)—, —S(O)₂—, —O—, or—N(R⁵)—; provided that when X is —N(R⁵)— and W is —S(O)—, —S(O)₂—, —O—,or —N(R⁵)—, then U is not a bond;

R¹, R² and R⁵ are independently selected from the group consisting of H,alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, —OR¹⁵, —CN, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹¹)(R¹²), —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂, —N═C(R⁸)₂and —N(R⁸)₂, provided that R¹ and R⁵ are not both selected from —NO₂,—N═C(R⁸)₂ and —N(R⁸)₂;

R³, R⁴, R⁶ and R⁷ are independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³),—N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸; provided that when U is —O— or —N(R⁵)—,then R³, R⁴, R⁶ and R⁷ are not halo, —SH, —OR⁹, —SR¹⁹, —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)C(O)N(R¹²)(R¹³), or —N(R¹¹)C(O)OR⁹; provided that when W is —O—or —N(R⁵)—, then R³ and R⁴ are not halo, —SH, —OR⁹, —SR¹⁹,—S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸,—N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), or —N(R¹¹)C(O)OR⁹; and providedthat when X is —N(R⁵)—, W is —C(O)— and U is a bond, R³ and R⁴ are nothalo, —CN, —SH, —OR⁹, —SR¹⁹, —S(O)N(R¹¹)(R¹²) or —S(O)₂N(R¹¹)(R¹²); orR³, R⁴, R⁶ and R⁷, together with the carbon to which they are attached,form a 3-7 membered cycloalkyl group optionally substituted by R¹⁴ or a3-7 membered cycloalkylether optionally substituted by R¹⁴;

or R³ and R⁴ or R⁵ and R⁷ together with the carbon to which they areattached, are combined to form multicyclic groups such as

wherein M is —CH₂—, S, —N(R¹⁹)— or O, A and B are independently aryl orheteroaryl and q is 0, 1 or 2 provided that when q is 2, one M must be acarbon atom and when q is 2, M is optionally a double bond; and with theproviso that when R³, R⁴, R⁶ and R⁷ form said multicyclic groups

then adjacent R³ and R⁴ or R⁶ and R⁷ groups cannot be combined to formsaid multicyclic groups;

R⁸ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R⁹ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R¹⁰ is independently selected from the group consisting of H, alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and—N(R¹⁵)(R¹⁶);

R¹¹, R¹² and R¹³ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,—C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹⁵)(R¹⁶),—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN;

R¹⁴ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkenyl and alkynyl groups in R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are independently unsubstitutedor substituted by 1 to 5 R²¹ groups independently selected from thegroup consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴,C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl,R²⁷-arylalkyl, R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁹,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl;

provided that when W is —C(O)— and U is a bond, R¹ is not optionallysubstituted phenyl, and that when U is —C(O)— and W is a bond, R⁵ is notoptionally substituted phenyl;

provided that neither R¹ nor R⁵ is —C(O)-alkyl-azetidinone or alkyldi-substituted with (—COOR¹⁵ or —C(O)N(R¹⁵)(R¹⁶)) and (—N(R¹⁵)(R¹⁶),—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),or —N(R¹⁵)C(O)OR¹⁶);

provided that when R¹ is methyl, X is —N(R⁵)—, R² is H, W is —C(O)— andU is a bond, (R³, R⁴) is not (H, H), (phenyl, phenyl), (H, phenyl),(benzyl, H), (benzyl, phenyl), (i-butyl, H), (i-butyl, phenyl),(OH-phenyl, phenyl), (halo-phenyl, phenyl), or (CH₃O-phenyl,NO₂-phenyl); and when W is a bond and U is —C(O)—, (R³, R⁴) is not (H,H), (phenyl, phenyl), (H, phenyl), (benzyl, H), (benzyl, phenyl),(i-butyl, H), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl,phenyl), or (CH₃O-phenyl, NO₂-phenyl);

provided that when X is —N(R⁵)—, R¹ and R⁵ are each H, W is —C(O)— and Uis a bond, (R³, R⁴) is not (optionally substituted phenyl, optionallysubstituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or(heteroaryl, heteroarylalkyl);

provided that when U is a bond, W is —C(O)—, and R³ and R⁴ form a ringwith the carbon to which they are attached, R¹ is not 2-CF₃-3-CN-phenyl;

provided that when X is —N(R⁵)—, U is —O— and W is a bond or—C(R⁶)(R⁷)—, (R³,R⁴) is not (H, —NHC(O)-alkyl-heteroaryl) or (H,alkyl-NHC(O)-alkyl-heteroaryl); and

provided that when X is —N(R⁵)—, R¹ and R⁵ are not-alkylaryl-aryl-SO₂—N(R¹⁵)(R¹⁶) wherein R¹⁵ is H and R¹⁶ is heteroaryl;

provided that when R¹ is R²¹-aryl or R²¹-arylalkyl, wherein R²¹ is—OCF₃, —S(O)CF₃, —S(O)₂CF₃, —S(O)alkyl, —S(O)₂alkyl, —S(O)₂CHF₂,—S(O)₂CF₂CF₃, —OCF₂CHF₂, —OCHF₂, —OCH₂CF₃, —SF₅ or —S(O)₂NR¹⁵R¹⁶;

wherein R¹⁵ and R¹⁵ are independently selected from the group consistingof H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,R¹⁸-alkyl, R¹⁸-cycloalkyl, R¹⁸-heterocycloalkyl, R¹⁸-aryl andR¹⁸-heteroaryl; U is a bond or —CH₂; and X is —N(R⁵)—; then R⁵ is H;

provided that when U is a bond,

R³ and R⁴ are alkyl,

where R²¹ is halo, —CN, alkyl, alkoxy, haloalkyl or haloalkoxy, or R³and R⁴, together with the carbon to which they are attached, form a 3-7membered cycloalkyl group,

and R¹ is

where a is 0 to 6 and R²² is alkyl, alkoxy, halo, —CN, —OH, —NO₂ orhaloalkyl;

then R^(21a) is not H, —C(O)₂R¹⁵, wherein R¹⁵ is selected from the groupconsisting of alkyl, cycloalkyl and alkyl substituted with phenyl, alkylor alkyl-R²² wherein R²² is selected from the group consisting of

phenyl,

phenyl substituted with alkyl,

and

wherein R²² is selected from the group consisting of H, methoxy, nitro,oxo, —OH, halo and alkyl,

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingaspartyl protease comprising administering at least one compound offormula I to a patient in need of such treatment.

More specifically, the invention comprises: the method of treating acardiovascular disease such as hypertension, renal failure, or a diseasemodulated by renin inhibition; the method of treating HumanImmunodeficiency Virus; the method of treating a cognitive orneurodegenerative disease such as Alzheimer's Disease; the method ofinhibiting plasmepins I and II for treatment of malaria; the method ofinhibiting Cathepsin D for the treatment of Alzheimer's Disease, breastcancer, and ovarian cancer; and the method of inhibiting protozoalenzymes, for example inhibition of plasmodium falciparnum, for thetreatment of fungal infections. Said method of treatment compriseadministering at least one compound of formula I to a patient in need ofsuch treatment. In particular, the invention comprises the method oftreating Alzheimer's disease comprising administering at least onecompound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treatingAlzheimer's disease comprising administering to a patient I need of suchtreatment a combination of at least one compound of formula I and acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist ina pharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's disease.

DETAILED DESCRIPTION

Compounds of formula I wherein X, W and U are as defined above includethe following independently preferred structures:

In compounds of formulas IA to IF, U is preferably a bond or—C(R⁶)(R⁷)—. In compounds of formula IG and IH, U is preferably —C(O)—.

It will be understood that since the definition of R¹ is the same as thedefinition of R⁵, when X is —N(R⁵)—, compounds of formula I wherein W isa bond and U is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —C(R⁶)(R⁷)— or—N(R⁵)— are equivalent to compounds of formula I wherein U is a bond andW is a bond, —S(O)—, —S(O)₂—, —C(O)—, —O—, —C(R⁶)(R⁷)— or —N(R⁵)—.

More preferred compounds of the invention are those of formula IBwherein U is a bond or those of formula IB wherein U is —C(R⁶)(R⁷)—.

Another group of preferred compounds of formula I is that wherein R² isH.

R³, R⁴, R⁶ and R⁷ are preferably selected from the group consisting ofalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³),—N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸.

R³, R⁴, R⁶ and R⁷ are preferably selected from the group consisting ofaryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl,heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.

In a group of preferred compounds

-   -   U is a bond or —C(O)—;    -   W is a bond or —C(O)—;    -   X is —N(R⁵)—;    -   R¹ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl,        cycloalkylalkyl, R²-cycloalkylalkyl, heterocycloalkyalkyl or        R²¹-heterocycloalkylalkyl,    -   R¹ is H;    -   R³ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or        R²¹-arylalkyl;    -   R⁴ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or        R²¹-arylalkyl;    -   R⁵ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl,        cycloalkylalkyl, R²¹-cycloalkylalkyl, heterocycloalkyalkyl or        R²¹-heterocycloalkylalkyl;    -   R⁶ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or        R²¹-arylalkyl;    -   R⁷ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl or        R²¹-arylalkyl;    -   R¹⁵, R¹⁶ and R¹⁷ is H, R¹⁸-alkyl, alkyl or

-   -   R²¹ is alkyl, aryl, halo, —OR¹⁵, —NO₂, —C(O)R¹⁵,        —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) or —CH(R¹⁵)(R¹⁶);    -   n is 1;    -   m is 1;    -   R¹⁸ is —OR²⁰    -   R²⁰ is aryl;        and    -   R²³ is alkyl.

In a group of preferred compounds

-   -   R³, R⁴, R⁶ and R⁷ are

and

-   -   R¹ and R⁵ is H, CH₃,

In an additional group of preferred compounds;

-   -   U is a bond or —C(O)—;    -   W is a bond or —C(O)—;    -   X is —N(R⁵)—;    -   R¹ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl,        cycloalkylalkyl, R²¹-cycloalkylalkyl, heterocycloalkyalkyl or        R²¹-heterocycloalkylalkyl,    -   R² is H;    -   R³ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl,        R²¹-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl,        heterocycloalkylalkyl, R²¹-heteroarylalkyl, R²¹-heteroaryl,        R²¹-heterocycloalkyl or R²¹-heterocycloalkylalkyl;    -   R⁴ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl,        R²¹-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl,        heterocycloalkylalkyl, R²¹-heteroarylalkyl, R²¹-heteroaryl,        R²¹-heterocycloalkyl or R²¹-heterocycloalkylalkyl;    -   R⁵ is H, alkyl, R²¹-alkyl, arylalkyl, R²¹-arylalkyl,        cycloalkylalkyl, R²¹-cycloalkylalkyl, heterocycloalkyalkyl or        R²¹-heterocycloalkylalkyl;    -   R⁶ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl,        R²¹-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl,        heterocycloalkylalkyl, R²¹-heteroarylalkyl, R²¹-heteroaryl,        R²¹-heterocycloalkyl or R²¹-heterocycloalkylalkyl;    -   R⁷ is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl,        R²¹-alkyl, R²¹-cycloalkylalkyl, R²¹-cycloalkyl, R²¹-aryl,        R²¹-arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl,        heterocycloalkylalkyl, R²¹-heteroarylalkyl, R²¹-heteroaryl,        R²¹-heterocycloalkyl or R²¹-heterocycloalkylalkyl;    -   R¹⁵, R¹⁶ and R¹⁷ is H, cycloalkyl, cycloalkylalkyl, R¹⁸-alkyl,        alkyl, aryl, R¹⁸-aryl, R¹⁸-arylalkyl, arylalkyl,

-   -   n is 1 or 2;    -   m is 0 or 1;    -   R¹⁸ is —OR²⁰ or halo;    -   R²⁰ is aryl or halo substituted aryl;    -   R²¹ is alkyl, aryl, heteroaryl, R²²-alkyl, R²²-aryl,        R²²-heteroaryl, halo, heterocycloalkyl, —N(R¹⁵)(R¹⁶), —OR¹⁵,        —NO₂, —C(O)R¹⁵, —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,        —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) or        —CH(R¹⁵)(R¹⁶);    -   R²² is —OR¹⁵ or halo        and    -   R²³ is H or alkyl.

It is noted that the carbons of formula I may be replaced with 1 to 3silicon atoms so long as all valency requirements are satisfied.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl. R²¹-substitutedalkyl groups include fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more substituents (e.g., R¹⁸, R²¹, R²², etc.) which may be the sameor different, and are as defined herein or two substituents on adjacentcarbons can be linked together to form

Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to eight of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R²¹substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore R²¹ substituents which may be the same or different, and are asdefined above. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like. Further non-limitingexamples of cycloalkyl include the following

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.The cycloalkenyl ring can be optionally substituted with one or more R²¹substituents which may be the same or different, and are as definedabove. Preferred cycloalkenyl rings contain about 5 to about 7 ringatoms. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 14 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclicazaheterocyclenyl groups include 1,2,3,4-tetrahydropyridine,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples ofsuitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting exampleof a suitable multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 14ring atoms, preferably about 5 to about 10 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R²¹ substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl areas previously described. Preferred aralkyls comprise a lower alkylgroup. Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein. Preferred arylcycloalkyls are those wherein aryl isphenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Thearylcycloalkyl can be optionally substituted by 1-5 R²¹ substituents.Non-limiting examples of suitable arylcycloalkyls include indanyl and1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Arylheterocycloalkyl” means a group derived from a fused aryl andheterocycloalkyl as defined herein. Preferred arylcycloalkyls are thosewherein aryl is phenyl and heterocycloalkyl consists of about 5 to about6 ring atoms. The arylheterocycloalkyl can be optionally substituted by1-5 R²¹ substituents. Non-limiting examples of suitablearylheterocycloalkyls include

The bond to the parent moiety is through a non-aromatic carbon atom.

Similarly, “heteroarylalkyl” “cycloalkylalkyl” and“heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- orheterocycloalkyl-alkyl- group in which the heteroaryl, cycloalkyl,heterocycloalkyl and alkyl are as previously described. Preferred groupscontain a lower alkyl group. The bond to the parent moiety is throughthe alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkynyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

The suffix “ene” on alkyl, aryl, heterocycloalkyl, etc. indicates adivalent moiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, orheteroarylalkyl moiety includes substitution on the ring portion and/oron the alkyl portion of the group.

When a variable appears more than once in a group, e.g., R⁸ in —N(R⁸)₂,or a variable appears more than once in the structure of formula I,e.g., R¹⁵ may appear in both R¹ and R³, the variables can be the same ordifferent.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Those skilled in the art will recognize that certain compounds offormula I are tautomeric, and all such tautomeric forms are contemplatedherein as part of the present invention. For example, a compound whereinX is —N(R⁵)— and R¹ and R⁵ are each H can be represented by any of thefollowing structures:

When R²¹ and R²², are, for example, —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and R¹⁵ andR¹⁶ form a ring, the moiety formed, is, for example,

The term “purified”, “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g. from a reaction mixture),or natural source or combination thereof. Thus, the term “purified”, “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization and the like),in sufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in Formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto. For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting aspartyl protease and/or inhibiting BACE-1 andthus producing the desired therapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, sulfates, sulfonates (such as those mentionedherein), tartarates, thiocyanates, toluenesulfonates (also known astosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of Formula (I) may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of Formula (I) as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention embraces all geometric andpositional isomers. For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula (I) cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can beheterocyclicaspartyl protease inhibitors.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

Compounds of formula I can be made using procedures known in the art.Preparative methods for preparing starting materials and compounds offormula I are show below as general reaction schemes (Method A, MethodB, etc.) followed by specific procedures, but those skilled in the artwill recognize that other procedures can also be suitable. In theSchemes and in the Examples below, the following abbreviations are used:

methyl: Me; ethyl: Et; propyl: Pr; butyl: Bu; benzyl: Bn; tertiarybutyloxycarbonyl: Boc or BOC

high pressure liquid chromatography: HPLC

liquid chromatography mass spectroscopy: LCMS

room temperature: RT or rt

day: d; hour: h; minute: min

retention time: R_(t).

microwave: μW

saturated: sat.; anhydrous: anhyd.

1-hydroxybenzotriazole: HOBt

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: EDCl

ethyl acetate: EtOAc

Benzyloxycarbonyl: CBZ

[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate)]: Selectfluor

1,8-diazabicyclo[5,4,0]undec-7-ene: DBU

tetrahydrofuran: THF; N,N-dimethylformamide: DMF; methanol: MeOH;diethyl ether: Et₂O; acetic acid: AcOH; acetonitrile: MeCN;trifluoroacetic acid: TFA; dichloromethane: DCM; dimethoxyethane: DME;diphenylphosphinoferrocene (dppf);

n-butyllithium: n-BuLi; lithium diisopropylamide: LDA

1-hydroxy-7-azabenzotriazole: HOAt

4-N,N-dimethylaminopyridine: DMAP; diisopropylethylamine: DIEA;N-methylmorpholine: NMM

Microporous Toluene sulfonic acid resin (MP-TsOH resin)

tris-(2-aminoethyl)aminomethyl polystyrene (PS-trisamine)

methylisocyanate polystyrene (PS—NCO)

Saturated (sat.); anhydrous. (anhyd); room temperature (rt); hour (h);Minutes (Min), Retention Time (Rt); molecular weight (MW); milliliter(mL); gram (g). milligram (mg); equivalent (eq); day (d); microwave(μW); microliter (μL);

All NMR data were collected on 400 MHz NMR spectrometers unlessotherwise indicated. LC-Electrospray-Mass spectroscopy with a C-18column and 5% to 95% MeCN in water as the mobile phase was used todetermine the molecular mass and retention time. The tables contain thecompounds with retention time/observed MW and/or NMR data.

For internal consistency in the reaction schemes shown in Methods A toDF, the product of each method is shown as structure A4, B4, C3, etc.,wherein certain variables are as defined for that method, but it will beapparent that, for example, A4 has the same structure as C3. That is,different methods can be used to prepare similar compounds.

The compounds in the invention may be produced by processes known tothose skilled in the art and as shown in the following reaction schemesand in the preparations and examples described below. The tables containthe compounds with observed m/e values from mass spectroscopy and/or NMRdata. These compounds can be obtained with synthetic methods similar tothese listed in the last column using appropriate reagents.

Method A

Method A, Step 1:

To a solution of A1 (R³═CH₃ & R⁴═CH₂CH(CH₃)₂) (10 mmol, 1 eq) in 30 mlof anhyd. CH₂Cl₂ was added thiocarbonyl dipyridone (1.2 eq). Afterstirring overnight the solution was diluted with CH₂Cl₂, washed with 1NHCl, H₂O (2×), and a saturated aqueous NaCl solution (2×). The organicsolution was dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified via flash chromatography to afford A2 (R³═CH₃ &R⁴═CH₂CH(CH₃)₂).

Method A, Step 2:

A solution of 3,5-difluorobenzyl amine (0.15 mmol, 1.5 eq) in THF (0.15mL) was added to a solution of A2 (R³═CH₃ & R⁴═CH₂CH(CH₃)₂) (0.1 mmol, 1eq) in anhydrous CH₂Cl₂ (1 mL). The reaction mixture was refluxedovernight. The reaction solution was added to MP-TsOH resin (2-3 eq) anddiluted with CH₃CN. The suspension was agitated overnight. The mixturewas filtered and the filtrate was concentrated to afford A3(R¹=3,5-difluorobenzyl, R³═CH₃, & R⁴═CH₂CH(CH₃)₂).

Method A, Step 3:

To a solution of A3 (R¹=3,5-difluorobenzyl, R³═CH₃, & R⁴═CH₂CH(CH₃)₂)(10 mg) in CH₃OH (1 mL) was added NH₄OH (0.44 mL) and t-butyl hydrogenperoxide (0.1 mL) and the reaction mixture was agitated for 2 d. Thesolution was concentrated, the resulting residue was dissolved in CH₃OH(1.2 mL) and was treated with sulfonic acid resin. The suspension wasagitated overnight and the resin was washed with CH₃OH (4×10 min) beforeit was treated with 2 N NH₃ in CH₃OH for 1 h. The suspension wasfiltered and the filtrate was concentrated to give the crude materialwhich was purified by preparative HPLC/LCMS eluting with a CH₃CN/H₂Ogradient to afford A4 (R¹=3,5-difluorobenzyl, R²═H, R³═CH₃, &R⁴═CH₂CH(CH₃)₂). NMR (CD₃OD): δ6.9, m, 3H, δ4.8-4.9, m; δ1.75, d, 2H,δ1.5, m, 1H, δ1.42, s, 3H, δ0.85, d, 3H, δ0.65, d, 3H. ES_LCMS (m/e)296.1.

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 1

223 224 2

223 224 3

225 226 4

225 226 5

227 228 6

237 238 7

239 240 8

239 240 9

239 240 10

240 241 11

241 242 12

241 242 13

251 252 14

253 254 15

254 255 16

255 256 17

255 256 18

255 256 19

260 261 20

260 261 21

265 266 22

265 266 23

265 266 24

267 268 25

268 269 26

268 269 27

269 270 28

273 274 29

273 274 30

274 275 31

274 275 32

274 275 33

277 278 34

279 280 35

280 281 36

280 281 37

280 281 38

280 281 39

281 282 40

282 283 41

282 283 42

282 283 43

283 284 44

285 286 45

287 288 46

287 288 47

289 290 48

293 294 49

294 295 50

294 295 51

295 296 52

296 297 53

301 302 54

303 304 55

304 305 56

304 305 57

305 306 58

307 308 59

307 308 60

308 309 61

310 311 62

317 318 63

319 320 64

322 323 65

324 325 66

327 328 67

327 328 68

327 328 69

327 328 70

328 329 71

330 331 72

331 332 73

331 332 74

335 336 75

335 336 76

337 338 77

337 338 78

342 343 79

345 346

80 345 346 81

349 350 82

349 350 83

351 352 84

351 352 85

351 352 86

359 360 87

361 362 88

361 362 89

361 362 90

363 364 91

363 364 92

363 364 93

363 364 94

363 364 95

363 364 96

369 370 97

374 375 98

375 376 99

375 376 100

377 378 101

377 378 102

377 378 103

381 382 104

382 383 105

385 386 106

385 386 107

386 387 108

389 390 109

391 392 110

391 392 111

391 392 112

391 392 113

393 394 114

393 394 115

400 401 116

401 402 117

401 402 118

401 402 119

401 402 120

403 404 121

403 404 122

403 404 123

405 406 124

405 406 125

409 410 126

409 410 127

409 410 128

409 410 129

411 412 130

413 414 131

413 414 132

414 415 133

415 416 134

415 416 135

415 416 136

417 418 137

419 420 138

421 422 139

423 424 140

425 426 141

425 426 142

425 426 143

427 428 144

429 430 145

430 431 146

430 431 147

431 432 148

433 434 149

437 438 150

439 440 151

440 441 152

440 441 153

441 442 154

441 442 155

442 443 156

447 448 157

449 450 158

455 456 159

463 464 160

463 464 161

471 472 162

473 474 163

481 482 164

481 482 165

487 488 166

488 489 167

499 500 168

504 505 169

523 524 170

525 526 171

525 526 172

527 528 173

528 529 174

535 536 175

535 536 176

535 536 177

535 536 178

550 551 179

554 555 180

556 557 181

569 570 182

581 582 183

374 NA 184

388 NA 185

337 NMR 186

351 NMR

Method B

A modified literature procedure was used (Ugi, I. Angew. Chem. 1962, 749-22).

Method B, Step 1:

To a solution of B1 (HCl salt, R¹=3-chlorophenethyl) (1.1 g, 5.73 mmol)in anhydrous CH₃OH (15 mL) was added potassium thiocyanate (0.56 g, 5.73mmol). The reaction mixture was heated to 60° C. for 1 h. The suspensionwas filtered and the filtrate was added to B5 (R³=Me, R⁴=^(i)Bu) (0.72mL, 5.73 mmol) and benzyl isocyanide (0.77 mL, 6.3 mmol). The mixturewas stirred overnight before the solution was concentrated and theresidue was purified via flash chromatography eluting with ethyl acetatein hexane to yield 0.28 g of B2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, andR¹=3-Chlorophenethyl).

Method B, Step 2:

A solution of 40% concentrated HCl in CH₃CH₂OH was added to B2 (R³═CH₃,R⁴═CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl) and the solution was heated ina microwave at 160° C. for 30 min. The solution was concentrated andpurified via reverse phase preparative HPLC eluting with a CH₃CN/H₂O(with 0.1% formic acid) gradient to afford B3 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,and R¹=3-Chlorophenethyl).

Method B, Step 3:

Compound B4 (R²═H, R₃═CH₃, R⁴═CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl) wasprepared from B3 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, and R¹=3-Chlorophenethyl)following a procedure similar to Method A, Step 3. NMR (CD₃OD): δ 8.1,br, 1H; δ 7.35, s, 1H; δ 7.25, m, 3H; δ 3.6, m, 1H; δ 3.4, m, 1H; δ 3.0,m, 1H; δ 2.8, m, 1H; δ 1.75, m, 1H; δ 1.6, m, 1H; δ 1.35, m, 1H; δ 1.2s, 3H; δ 0.8, m, 6H. ES_LCMS (m/e): 308.1

The following compounds were prepared using similar methods

Obs. # Structure MW m/e 545

251 252 546

293 294 547

307 308 548

357 358 549

371 372 550

413 551

265

Method C

Method C, Step 1:

A solution of C1 (R³═R⁴═CH₂CH₂CH₂CH₃) (50 mg, 0.25 mmol) and C4(R¹=3-chlorophenyl) (38 μL, 0.26 mmol) was refluxed overnight. Trisamineresin (2 eq) and polystyrene isocyanate resin (2 eq) was added and themixture was agitated. After 3 h, the suspension was filtered and theresin was washed with CH₂Cl₂ (3×) and CH₃OH (3×). The filtrate wasconcentrated to afford C2 (R¹=3-Cl—C₆H₄, R³═R⁴═CH₂CH₂CH₂CH₃) (60 mg,68%).

Method C, Step 2:

Compound C3 (R¹=3-Cl—C₆H₄, R²═H, R³═R⁴═CH₂CH₂CH₂CH₃) was prepared fromC2 (R¹=3-Cl—C₆H₄, R³═R⁴═CH₂CH₂CH₂CH₃) following a procedure similar toMethod A, Step 3. NMR (CDCl₃): δ 7.4, m, 2H; δ 7.2, m, 2H; δ 5.0, s, 2H;δ 1.7, m, 4H; δ 1.1, m, 8H; δ 0.7; m, 6H. ES-LCMS (m/e): 336.1.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 641

209 210 642

211 212 643

215 216 644

225 226 645

239 240 646

245 246 647

246 247 648

251 252 649

267 268 650

309 310 651

317 318 652

319 320 653

323 324 654

324 325 655

329 330 656

329 330 657

335 336 658

335 336 659

335 336 660

335 336 661

335 336 662

352 353 663

352 353 664

377 378 665

385 386 666

391 392 667

420 421 668

420 421

Method D

Method D, Step 1:

A mixture of D1 (R³═R⁴═CH₂C₆H₅) (20 g), potassium cyanide (40 g) andammonium carbonate (15 g) in ethanol (100 mL) and H₂O (200 mL) washeated in a sealed flask at 130° C. overnight to yield 25 g of D2(R³═R⁴═CH₂C₆H₅) after filtration followed by washing with water.

Method D, Step 2:

A solution of 2 N KOH (3 eq) was added to D2 (R³═R⁴═CH₂C₆H₅) (1 eq) andirradiated via microwave at 185° C. for 3 h followed by addition ofconcentrated HCl to the solution until a pH=2-3 was obtained. The solidwas filtered and washed with water to afford D3 (R³═R⁴═CH₂C₆H₅).

Method D, Step 3:

A solution of trimethylsilyldiazomethane in hexane (2 N) (2 eq) wasadded drop wise to a solution of D3 (R³═R⁴═CH₂C₆H₅) (1 eq) in anhydrousCH₃OH (30 mL). After 1 h, an additional 2 eq oftrimethylsilyldiazomethane in hexane (2 N) was added and the reactionwas stirred for 20 minutes before it was concentrated. The residue wasdissolved in a 0.2 N HCl solution (25 mL) and washed with ether (3×). Asaturated solution of Na₂CO₃ was added to the aqueous phase until the pHof the solution was basic. The solution was extracted with ethyl acetate(3×). The organic extracts were combined, dried over Na₂SO₄, andconcentrated to afford D4 (R³═R⁴═CH₂C₆H₅).

The following amino esters were prepared using a similar method.

Method E

Method E, Step 1:

Thionyl chloride (0.47, 6.38 mmol) was added drop wise to a solution ofE1 (R³═CH₂CH₂C₆H₅) (2 g, 6.38 mmol) and benzaldehyde dimethyl acetal(0.96 mL, 6.38 mmol) in anhydrous THF at 0° C. under N₂. After 5 min,ZnCl₂ (0.87 g, 6.38 mmol) was added and the reaction mixture was stirredat 0° C. After 3 h, an additional amount of ZnCl₂ (0.18 g, 1.28 mmol)and thionyl chloride (0.1 mL, 1.28 mmol) were added and stirred for 1 hat 0° C. The reaction mixture was poured into a stirred suspension ofice/H₂O. The mixture was stirred occasionally until the ice melted. Theaqueous solution was extracted with ether (3×). The combined organicextracts were washed with H₂O (3×), a sat. aqueous solution of NaHCO₃(1×), and H₂O (2×). The organic solution was dried over Na₂SO₄, filteredand concentrated. The crude material was purified via flashchromatography eluting with ethyl acetate in hexane to yield compound E2(R³═CH₂CH₂C₆H₅).

Method E, Step 2:

A solution of lithium hexamethyldisilazide in hexane (1.0 M, 1.65 mL,1.64 mmol) was added drop wise to a solution of E2 (R³═CH₂CH₂C₆H₅) (600mg, 1.49 mmol) and HMPA (0.85 mL) in THF (6.5 mL) cooled at −78° C.under N₂. After 15 min, isobutyl iodide (0.52 mL, 4.48 mmol) was addeddrop wise and the reaction mixture was stirred at −78° C. for 3 h. Thereaction was warmed to −65° C., stirred for 2 h and warmed to rtovernight. The reaction solution was poured into a mixture of sat.NaHCO₃ (aq)/ether/ice. The aqueous layer was extracted with ether (3×).The organic extracts were combined and washed with brine (2×). Theorganic solution was dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified via flash chromatography eluting with ethylacetate in hexane to yield compound E3 (R³═CH₂CH₂C₆H₅, R⁴═CH₂CH(CH₃)₂).

Method E, Step 3:

A solution of lithium methoxide (1 N in CH₃OH) (0.36 mL, 0.36 mmol) wasadded to compound E3 (R³═CH₂CH₂C₆H₅, R⁴═CH₂CH(CH₃)₂). The reactionmixture was shaken at rt for 50 min. An additional 0.55 eq of lithiummethoxide were added. After 2.5 h, a sat. aqueous solution of NaHSO₃(0.75 mL) and ethyl acetate (3 mL) was added to the reaction mixture andshaken for 15 min. The suspension was filtered. The resulting whitesolid was washed with a sat. aqueous solution of NaHSO₃ (1×) and ethylacetate (1×). The aqueous phase of the filtrate was separated andextracted with ethyl acetate (2×). The organic extracts were combinedand washed with a sat. aqueous solution of NaHSO₃ (8×). The organicsolution was dried over Na₂SO₄, filtered and concentrated to afford E4(R³═CH₂CH₂C₆H₅, R⁴═CH₂CH(CH₃)₂) (109 mg, 87%).

Method E, Step 4:

To a solution of E4 (R³═CH₂CH₂C₆H₅, R⁴═CH₂CH(CH₃)₂) (109 mg, 0.28 mmol)in CH₃OH (4 mL) was added 1 N HCl (0.28 mL, 0.28 mmol) and 20% palladiumhydroxide on carbon (22 mg). The reaction mixture was hydrogenated at 40psi. After 2.5 h, the reaction was filtered and the catalyst was washedwith CH₃OH (3×). The filtrate was concentrated to afford E5(R³═CH₂CH₂C₆H₅, R⁴═CH₂CH(CH₃)₂) (78 mg, 96%).

The following aminoesters were prepared using similar method.

Method F

A 500 mL methanol solution of 20 g of D5 (R³=benzyl, n=1) with 1.5 eq ofHCl was hydrogenated with 1 g of Rh/C (5% w/w) and 2 g of Pt/C (5% w/w)at 60 psi for 2 days. The solid was filtered and washed with excessivemethanol. The combined solution was evaporated to give 20 g of F1(R³=cyclohexylmethyl, n=1) as HCl salt.

The following amino esters were examples prepared using similar method.

Method G

Method G, Step 1:

To a solution of G1 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃) (400 mg, 1.23 mmol,generated following a procedure similar to Method C, Step 1) in ethanol(5 mL) was added lithium hydroxide monohydrate (100 mg, 2.45 mmol) inH₂O (0.5 mL). After 2.5 h, another portion of lithium hydroxidemonohydrate (100 mg, 2.45 mmol) was added. After 5.5 h, the reactionmixture was diluted with H₂O (15 mL) and extracted with ether (2×). Asolution of 30% HCl was added to the aqueous phase until its pH=1 to 2.The solution was saturated with NaCl and extracted with ethyl acetate(3×). The organic solution was dried over Na₂SO₄, filtered andconcentrated to afford G2 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃) (357 mg, 93%).

Method G, Step 2:

A solution of benzyl amine (1.2 eq) was added to G2 (R¹═CH₂(3-ClC₆H₄)and R³═CH₃) (1 eq), HOBT (1.5 eq) and polystyrene EDC resin (94 mg, 1.53mmol/g, 3 eq) in 1:1 THF:CH₃CN (1 mL). The reaction mixture was shakenovernight at rt. Trisamine resin (85 mg, 3.38 mmol/g, 6 eq) andisocyanate resin (100 mg, 1.47 mmol/g, 3 eq) was added. After 6 h, thesuspension was filtered and the filtrate was concentrated to afford G3(R¹═CH₂(3-ClC₆H₄), R³═CH₃, R¹⁵═CH₂C₆H₅ and R¹⁶═H).

Method G, Step 3:

Compound G4 (R¹═CH₂(3-ClC₆H₄), R²═H, R₃═CH₃, R¹⁵═CH₂C₆H₅ and R¹⁵═H) wasprepared from G3 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, R¹⁵═CH₂C₆H₅ and R¹⁶═H)following a procedure similar to Method A, Step 3.

The following compounds were prepared using similar methods.

Obs. # Structure MW m/e 669

322 323 670

334 335 671

336 337 672

348 349 673

364 365 674

364 365 675

376 377 676

384 385 677

390 391 678

393 394 679

398 399 680

398 399 681

406 407 682

412 413 683

414 415 684

414 415 685

414 415 686

421 422 687

428 429 688

434 435 689

442 443 690

449 450 691

461 462 692

511 512 693

511 512

Method H

Method H, Step 1:

To a solution of H1 (R³═CH₃) (5 g, 39 mmol) in a 1:1 mixture of 0.5 MNaHCO₃:CH₃CH₂OH was added R¹—NCS(R¹=3-chlorobenzyl) (11.5 mL, 78 mmol).The reaction mixture was heated at 50° C. overnight. The reaction wascooled and diluted with water. The aqueous phase was extracted withethyl acetate (5×). The organic extracts were combined, washed withwater (2×) and dried over Na₂SO₄. The solution was filtered and solventwas removed to give a small volume of solution. Hexane was added and theresulting suspension was filtered to yield 6.8 g of a solid H2 (R³═CH₃,R¹═CH₂(3-ClC₆H₄)) (61%).

Method H, Step 2:

Compound H3 (R³═CH₃, R¹═CH₂(3-ClC₆H₄)) was synthesized from H2 (R³═CH₃,R¹═CH₂(3-ClC₆H₄)) following a procedure similar to Method A, Step 3.

Method H, Step 3:

To a solution of crude H3 (R³═CH₃, R¹═CH₂(3-ClC₆H₄)) (14 mmol) in a 1:3mixture of CH₃OH:THF was added 0.5 M NaHCO₃ in H₂O (28 mL, 14 mmol) anddi-tert-butyl dicarbonate (3.69 g, 16.9 mmol). The reaction was stirredat rt for 2.5 h and then stored at −10° C. overnight. The reaction wasdiluted with brine and extracted with ethyl acetate (4×). The organicextracts were combined and washed with brine (1×). The organic solutionwas dried over Na₂SO₄, filtered and concentrated. The crude material waspurified via flash chromatography eluting with ethyl acetate in hexaneto afford 1.5 g of H4 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃).

Method H, Step 4:

A solution of triflic anhydride (128 μL, 0.76 mmol) in CH₂Cl₂ (5 mL) wasadded drop wise to a solution of H4 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃) (200mg, 0.55 mmol) and 2,6-lutidine (176 μL, 2.18 mmol) at −30° C. Thereaction mixture was stirred for 1.5 h. Water (10 mL) was added at −20°C. and the ice bath was removed. The reaction was stirred until itreached 0° C. The organic layer was separated, dried over Na₂SO₄,filtered and concentrated to afford 310 mg of H5 (R¹═CH₂(3-ClC₆H₄) andR³═CH₃).

Method H, Step 5:

A solution of crude H5 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃) (0.11 mmol) and 7Nammonia in Methanol (R²¹—H═NH₂—H) (10 eq) was stirred overnight at rt.The reaction solution was concentrated. The crude material was purifiedusing reverse phase preparative HPLC eluting with a CH₃CN/H₂O gradientwith 0.1% formic acid to yield H6 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, R²¹═NH₂).

Method H, Step 6:

A solution of 50% trifluoroacetic acid in CH₂Cl₂ (2 mL) was added to H6(R¹═CH₂(3-ClC₆H₄), R³═CH₃, R²¹═NH₂). After 40 min the solvent wasevaporated and residue purified by preparative HPLC/LCMS eluting with aCH₃CN/H₂O gradient to afford H7 (R¹═CH₂(3-ClC₆H₄), R₃═CH₃, R²¹═NH₂). NMR(CDCl₃), δ 7.45, m, 3H; δ 7.35, m, 1H; δ 4.9, m, 2H; δ 3.5, m, 2H; δ1.65, s, 3H. ES_LCMS (m/e) 267.07.

The following compounds were prepared using similar methods.

Obs. # Structure MW m/e 694

238 239 695

248 249 696

257 258 697

264 265 698

266 267 699

292 293 700

308 309 701

314 315 702

320 321 703

328 329 704

334 335 705

342 343 706

354 355 707

372 373 708

418 419 709

483 484

Method I

Method I, Step 1:

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution ofthe formate salt of I1 (R¹═CH₂(3-ClC₆H₄), R³═CH₃ and R¹⁶═H) in CH₂Cl₂and the suspension was agitated. After 15 min, the mixture was filteredand the resin was washed with CH₂Cl₂ (4×). The filtrate was concentratedto afford the free base I1 (R¹═CH₂(3-ClC₆H₄), R³═CH₃ and R¹⁶═H).

A solution of R¹⁵COOH(R¹⁵=Phenethyl) (1.3 eq) was added to a mixture ofEDC resin (41 mg, 1.53 mmol/g, 3 eq), HOBT (1.5 eq), and the free baseof I1 (R¹═CH₂(3-ClC₆H₄), R³═CH₃ and R¹⁶═H) (0.021 mmol) in 1:1CH₃CN:THF. The suspension was agitated overnight. Polystyrene isocyanateresin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1mixture of CH₃CN:THF (0.5 mL) was added. The mixture was agitated for 6h. The suspension was filtered and the filtrate was concentrated toafford I2 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, R¹⁶═H and R¹⁵═CH₂CH₂C₆H₅).

Method I, Step 2:

I3 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, R¹⁶═H and R¹⁵═CH₂CH₂C₆H₅) was preparedfrom I2 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, R¹⁶═H and R¹⁵═CH₂CH₂C₆H₅) usingmethod similar to method H step 6.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 710

280 281 711

308 309 712

308 309 713

334 335 714

342 343 715

362 363 716

372 373 717

376 377 718

398 399 719

406 407 720

410  11 721

410  11 722

414  15 723

420  21 724

428  29 725

511  12

Method J

Method J, Step 1:

Diethylaminomethyl polystyrene resin (5 eq) was added to a solution ofJ1 (TFA salt, R¹═CH₂(3-ClC₆H₄) and R³═CH₃) in CH₂Cl₂ and the suspensionwas agitated. After 15 min, the mixture was filtered and the resin waswashed with CH₂Cl₂ (4×). The filtrate was concentrated to afford thefree base. A solution of R¹⁵NCO(R¹⁵=butyl) (2 eq) in CH₂Cl₂ was added tothe free base of J1 (R¹═CH₂(3-ClC₆H₄) and R³═CH₃) (0.021 mmol) in 1:1CH₃CN:THF. The suspension was agitated overnight. Polystyrene isocyanateresin (45 mg, 3 eq), polystyrene trisamine resin (40 mg, 6 eq) and a 1:1mixture of CH₃CN:THF (0.5 mL) was added. The mixture was agitated for 6h. The suspension was filtered and the filtrate was concentrated toafford J2 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, and R¹⁵═CH₂CH₂CH₂CH₃).

Method J, Step 2:

Compound J3 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, and R¹⁵═H₂CH₂CH₃) was preparedfrom J2 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, and R¹⁵═CH₂CH₂CH₃) following theprocedure described in Method H, Step 2.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 726

323 324 727

337 338 728

| 352 729

358 730

365 366 731

377 378 732

413 414 733

417 418 734

421 422 735

425 426

Method K

Method K, Step 1:

A solution of R¹⁵SO₂Cl (R¹⁵=Propyl) (1.5 eq) was added to a suspensionof polystyrene diisopropylethylamine resin (18 mg, 3.45 mmol/g, 3 eq)and the free base of K1 prepared using method H(R¹═CH₂(3-ClC₆H₄) andR³═CH₃) (0.021 mmol) in 1:1 CH₃CN:THF. The suspension was agitatedovernight. Polystyrene isocyanate resin (45 mg, 3 eq), polystyrenetrisamine resin (40 mg, 6 eq) and a 1:1 mixture of CH₃CN:THF (0.5 mL)was added. The mixture was agitated for 6 h. The suspension was filteredand the filtrate was concentrated to afford K2 (R¹═CH₂(3-ClC₆H₄),R³═CH₃, and R¹⁵═CH₂CH₂CH₃).

Method K, Step 2:

Compound K3 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, and R¹⁵═CH₂CH₂CH₃) was preparedfrom K2 (R¹═CH₂(3-ClC₆H₄), R³═CH₃, and R¹⁵═CH₂CH₂CH₃) following theprocedure described in Method H, Step 6.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 736

316 317 737

344 345 738

372 373 739

378 379 740

442 443 741

454 455 742

492 493

Method L

(In the scheme, —Z—NH—C(O)R¹⁶— is equivalent to R¹ substituted by R²¹,or R¹ Substituted by alkyl-R²², wherein R²¹ and R²² are —N(R¹⁵)C(O)R¹⁶and R¹⁵ is H, and wherein Z is optionally substituted alkylene-arylene,alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method L, Step 1:

A solution of L1 (R³═CH₃ and R⁴═CH₂CH(CH₃)₂) (1 eq) andZ═-para-methylene-benzyl) (1.05 eq) in CH₂Cl₂ was stirred at rt. Thereaction solution was concentrated and purified via flashchromatography. The material was treated with 50% trifluoroacetic acidin CH₂Cl₂ for 30 min. The solution was concentrated. The residue wasdissolved in 1 N HCl (10 mL) and washed with ether (2×). A saturatedsolution of Na₂CO₃ in H₂O was added to the aqueous phase until thesolution became basic. The solution was extracted with CH₂Cl₂ (3×). TheCH₂Cl₂ extracts were combined, dried over Na₂SO₄, filtered andconcentrated to yield L2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z═para-(CH₂)C₆H₄(CH₂)—).

Method L, Step 2:

Compound L3 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z═para-(CH₂)C₆H₄(CH₂)—,R¹⁶═CH₂CH₂CH₂CH₃) was prepared from L2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z═para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method I,Step 1.

Method L, Step 3:

Compound L4 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z═para-(CH₂)C₆H₄(CH₂)—,R¹═CH₂CH₂CH₂CH₃) was prepared from (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z═para-(CH₂)C₆H₄(CH₂)—, R¹⁶═CH₂CH₂CH₂CH₃) following the proceduredescribed in Method A, Step 3.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 743

316 317 744

316 317 745

330 331 746

330 331 747

344 345 748

344 345 749

358 359 750

358 359 751

386 387 752

386 387 753

386 387 754

400 401 755

400 401 756

420 421 757

434 435 758

434 435 759

436 437 760

436 437 761

450 451 762

450 451 763

450 451 764

450 451 765

464 465 766

464 465 767

470 471 768

478 479 769

478 479 770

484 485 771

484 485 772

492 493 773

492 493 774

519 520 775

519 520 776

533 534 777

533 534

Method M

(In the scheme, —Z—NH—C(O)—NHR¹⁵— is equivalent to R¹ substituted byR²¹, or R¹ Substituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁶)—C(O)—NHR¹⁵ and R¹⁶ is H, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method M, Step 1:

Compound M2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z═para-(CH₂)C₆H₄(CH₂)—,R¹⁵=3,4-difluorophenyl) was prepared from M1 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z═para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method J,Step 1.

Method M, Step 2:

Compound M3 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z═para-(CH₂)C₆H₄(CH₂)—,R¹⁵=3,4-difluorophenyl) was prepared from M2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z═para-(CH₂)C₆H₄(CH₂)—, R¹⁵=3,4-difluorophenyl) following the proceduredescribed in Method A, Step 3. NMR (CD₃OD) δ 7.45, m, 1H; δ 7.26, m, 4H,7.24, m, 1H, δ 6.96, m, 1H, δ 4.8, m; δ 4.3, s, 2H, δ 1.69, m, 2H, δ1.44, m, 1H; δ 1.37, s, 3H; δ 0.8, m, 3H; δ 0.63, m, 3H. ES_LCMS (m/e)430.27

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 778

331 332 779

359 360 780

359 360 781

373 374 782

373 374 783

373 374 784

373 374 785

387 388 786

387 388 787

387 388 788

387 388 789

401 402 790

401 402 791

405 406 792

407 408 793

407 408 794

407 408 795

413 414 796

413 414 797

418 419 798

418 419 799

421 422 800

421 422 801

421 422 802

421 422 803

421 422 804

421 422 805

421 422 806

421 422 807

423 424 808

423 424 809

423 424 810

423 424 811

425 426 812

425 426 813

427 428 814

429 430 815

429 430 816

429 430 817

432 433 818

432 433 819

432 433 820

433 434 821

433 434 822

435 436 823

435 436 824

435 436 825

435 436 826

435 436 827

435 436 828

435 436 829

437 438 830

437 438 831

437 438 832

437 438 833

437 438 834

437 438 835

437 438 836

439 440 837

439 440 838

439 440 839

441 442 840

441 442 841

441 442 842

441 442 843

443 444 844

443 444 845

443 444 846

447 448 847

447 448 848

449 450 849

450 451 850

450 451 851

450 451 852

451 452 853

451 452 854

451 452 855

452 453 856

453 454 857

453 454 858

455 456 859

455 456 860

455 456 861

457 458 862

457 458 863

457 458 864

458 459 865

458 459 866

460 461 867

461 462 868

461 462 869

461 462 870

461 462 871

461 462 872

461 462 873

461 462 874

463 464 875

466 467 876

466 467 877

467 468 878

469 470 879

469 470 880

471 472 881

471 472 882

472 473 883

472 473 884

475 476 885

475 476 886

475 476 887

475 476 888

475 476 889

475 476 890

475 476 891

475 476 892

475 476 893

475 476 894

475 476 895

475 476 896

477 478 897

477 478 898

479 480 899

479 480 900

480 481 901

483 484 902

483 484 903

485 486 904

485 486 905

485 486 906

485 486 907

485 486 908

489 490 909

489 490 910

489 490 911

491 492 912

493 494 913

493 494 914

493 494 915

493 494 916

496 497 917

496 497 918

497 498 919

497 498 920

499 500 921

501 502 922

501 502 923

502 503 924

502 503 925

502 503 926

502 503 927

503 504 928

505 506 929

507 508 930

507 508 931

507 508 932

509 510 933

509 510 934

509 510 935

510 511 936

511 512 937

511 512 938

514 515 939

515 516 940

515 516 941

519 520 942

519 520 943

522 523 944

523 524 945

523 524 946

525 526 947

527 528 948

529 530 949

533 534 950

537 538 951

539 540 952

543 544 953

545 546 954

545 546 955

547 548 956

549 550 957

553 554 958

555 556 959

559 560 960

559 560 961

387

Method N

(In the scheme, —Z—NH—S(O)₂R¹⁶— is equivalent to R¹ substituted by R²¹,or R¹ Substituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁶)—C(O)—NHR¹⁵ and R¹⁶ is H, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method N, Step 1:

Compound N2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁶═CH₂CH(CH₃)₂) was prepared from N1 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—) following the procedure described in Method K,Step 1.

Method N, Step 2:

Compound N3 (R³═CH₃, R⁴═CH₂CH(CH₃)₂, Z=para-(CH₂)C₆H₄(CH₂)—,R¹⁶═CH₂CH(CH₃)₂) was prepared from N2 (R³═CH₃, R⁴═CH₂CH(CH₃)₂,Z=para-(CH₂)C₆H₄(CH₂)—, R¹⁶═CH₂CH(CH₃)₂) following the proceduredescribed in Method A, Step 3.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 962

380 381 963

380 381 964

394 395 965

394 395 966

451 452 967

484 485 968

484 485 969

498 499 970

498 499

Method O

Method O, Step 1:

A solution of indole-6-methanol (400 mg, 2.72 mmol),tert-butyldimethylsilyl choride (816 mg, 5.41 mmol) and imidazole (740mg, 10.9 mmol) in CH₂Cl₂ was stirred at rt. overnight before the solventwas evaporated and residue chromatographed using ethylacetate/hexane togive product O2.

Method O, Step 2:

To a solution of O2 (200 mg, 0.77 mmol) in THF (10 mL) at −78° C. wasadded butyl lithium (1.2 eq). The solution was stirred at −78° C. for 5min and then warmed to rt. The reaction mixture was cooled to −78° C.and p-toluenesulfonyl chloride was added. The solution was warmed to rtand stirred overnight. The reaction was quenched with a saturatedaqueous K₂CO₃ solution, extracted with ethyl acetate and CH₂Cl₂. Thecrude material was purified via flash chromatography usingethylacetate/hexane to afford 360 mg of O3.

Method O, Step 3:

A solution butyl lithium (1.2 eq) was added to a solution of O3 (340 mg,0.829 mmol) in THF (20 mL). The reaction mixture was stirred for 15 minat −78° C. then sulfur dioxide was bubbled through the solution for 15min. Hexane (100 mL) was added to the reaction mixture. The reactionmixture was evaporated to afford O4 which was used in the next stepwithout further purification.

Method O, Step 4:

To a solution of O4 (0.829 mmol) in CH₂Cl₂ cooled to 0° C. was addedN-chlorosuccinimide (220 mg, 1.66 mmol). After 2 h of stirring, thesolution was filtered through a Celite plug. The filtrate wasconcentrated to afford O5.

Method O, Step 5:

To a solution of O5 in anhydrous pyridine (3 mL) was added butyl amine(100 μL). The reaction was agitated at rt for 4 d. The reaction mixturewas partitioned between 1 N HCl and CH₂Cl₂. The organic layer wasseparated and washed with 1 N HCl (3×). The organic solution was driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedvia flash chromatography using ethylacetate/hexane to yield O6.

Method O, Step 6:

To a solution of O6 (70 mg) in THF was added TBAF. The reaction wasstirred at rt. before the reaction mixture was chromatographed usingethylacetate/hexane to afforded 50 mg of O7 (95%).

Method O, Step 7:

To a solution of O7 (50 mg) in CH₂Cl₂ (5 mL) was added thionyl chloride(1 mL) the reaction was stirred for 5 min and then evaporated to affordO8.

Method O, Step 8:

To a solution of O8 in CH₃OH (5 mL) was added sodium azide (50 mg). Thesolution was stirred at rt overnight and solvent evaporated. The residuewas chromatographed using ethylacetate/hexane to afforded O9 afterpurification.

Method O, Step 9:

To a suspension of O9 (70 mg) in CH₃OH was added 1 eq HCl (aq) andpalladium on carbon. The reaction mixture was hydrogenated at 1 atm for20 min to yield 90 mg of crude product O10.

Method O, Step 10:

A solution of lithium hydroxide (30 mg) in H₂O was added to a solutionof O10 (40 mg) in CH₃OH (3 mL). The reaction was stirred at rt for 2 hand an additional portion of LiOH (40 mg) was added and solution wasstirred for 2 more hours. The solvent was evaporated and residuechromatographed using ethylacetate/hexane to afforded O11.

Method P

Method P, Step 1:

A 300 mL of THF solution of 100 g of P1 (R²³=n-Pr) was added to asuspension of 38 g of LAH in 2 L of anhydrous THF at 0 C. The reactionmixture is stirred at r.t. for 1 h before 30 ml of H₂O, 90 ml of 15%NaOH was added at 0° C. The mixture was stirred at r.t. for one hourbefore Na₂SO₄ (anh) was added, the mixture was filtered, and thesolution evaporated to give a product which was dried under vacuoovernight. This product was dissolved in 600 ml of DCM and the solutionwas added into a solution of oxalyl chloride (37.3 ml) and DMSO (60.8ml) in 1.4 L of DCM at −78° C. over 40 min before Diisopropylethylamine(299 ml) was added at −78° C. The reaction was allowed to reach −10° C.The reaction was quenched with 1 L H₂O at −10° C. and the mixture wasextracted with DCM. After removal of solvent, P2 (R²³═Pr, 106 g) wasobtained. The crude material was used for next step withoutpurification.

Method P, Step 2:

To a 1.5 L DCM solution of P2 (R²³═Pr, 106 g) was addedp-Boc-aminomethylbenzylamine (1.1 eq) and sodium triacetoxyborohydride(1.1 eq) and the reaction was stirred at r.t. overnight. The reactionwas quenched with H₂O and content extracted with DCM. After removal ofsolvents the residue was chromatographed using a silica gel columneluted with 3% MeOH in DCM to give 42.5 g of P3 (R²³═Pr).

Method P, Step 3:

A 10 ml MeOH solution of P3 (R²³═Pr, 110 mg) was hydrogenated using Pd/C(5%, 11 mg) at 1 atm of hydrogen to give product P4 (R²³═Pr) afterremoval of solvent and catalyst.

Method P, Step 4:

To a 10 ml DCM solution of P4 at 0° C. (R₂₃═Pr) was added triphosgene(1.2 eq) and triethylamine (2.4 eq) and the solution was stirred at 0 Cfor 2 h before the reaction was extracted with DCM/H2O. After removal ofthe solvent, the residue was chromatographed using a silica gel columneluted with EtOAc/Hexane to give a white solid which was treated with 2NHCl in dioxane for 2 h. After removal of the solvent, compound P5(R²³═Pr) as a white solid was obtained (80 mg).

The following compounds were synthesized using similar methods:

Method Q

Method Q, Step 1:

At room temperature, Q1 (R³=Me; R⁴=iBu) (1.00 g) and Q8 (n=1, p=2, m=1)(1.24 g) in dichloromethane (30 mL) were stirred for 42 h. This mixturewas concentrated in vacuo to give an amber oil which was purified on acolumn of silica gel (200 mL) eluted with ethylacetate/hexane to give Q2(n=1, p=2, m=1, R³=Me; R⁴=iBu), a colorless oil (1.59 g).

Method Q, Step 2:

Compound Q3 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=iBu) was prepared from Q2(n=1, p=2, m=1, R³=Me; R⁴=iBu) using method similar to method A step 3.

Method Q, Step 3:

Compound Q3 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=iBu) (1.37 g) in anhydrousdichloromethane (25 mL) was treated with di-tert-butyl dicarbonate (0.68g, 1.1 equiv.) and diisopropylethylamine (0.66 mL, 1.1.equiv.). Theresulting solution was stirred at room temperature for 20 h before itwas diluted with dichloromethane and washed with 1N hydrochloric acid.The dried dichloromethane solution was concentrated in vacuo to give acolorless film (1.32 g) which was purified on a column of silica gel(125 mL) and eluted with hexane:ethyl acetate to give compound Q4 (n=1,p=2, m=1, R²═H, R³=Me; R⁴=i-Bu) as a white foam (0.74 g).

Method Q, Step 4:

Compound Q4 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu) (0.540 g) inabsolute EtOH (20 mL) was hydrogenated with 10% Pd/C (0.400 g) at 1 atmfor 2 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give Q5 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu)as a colorless oil (0.35 g).

Method Q, Step 5:

Compound Q5 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=iBu) (0.012 g) and HOBt(0.005 g) dissolved in acetonitrile (0.8 mL) and tetrahydrofuran (0.25mL) was treated with EDC resin (0.080 g, 3 eq., 1.53 mmol/g) in amicrotiter plate well followed by addition of a 1M dichloroethanesolution of R¹⁵—COOH (40 uL, 1.25 eq.). After the well was capped andshaken for 18 h, the mixture was filtered and the resin washed withacetonitrile (0.5 mL). The combined solution was treated with Trisamineresin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin (0.067 g, 3eq., 1.53 mmol/g) for 18 h before the solution was filtered and thesolvent was removed in vacuo to give Q6 (n=1, p=2, m=1, R²═H, R³=Me;R⁴=^(i)Bu, R¹⁵=Me).

Method Q, Step 6:

A dichloromethane solution (1.0 mL) of Q6 (n=1, p=2, m=1, R²═H, R³=Me;R⁴=^(i)Bu, R¹⁶=Me) was mixed with trifluoroacetic acid (1.0 mL) and thesolution was shaken for 2 h before it was concentrated. Diethyl ether(0.5 mL) was added and then concentrated in vacuo to give a residue,which was purified on a Prep LCMS unit to give Q7 (=1, p=2, m=1, R₂═H,R₃═Me; R₄=iBu, R₁₅=Me). NMR (CDCl₃): δ 8.38, br, 2H; δ 4.56, m, 1H; δ3.79, m, 1H; δ 3.57, m, 2H; δ 2.99, m, 1H; δ 2.48, m, 1H; δ 2.04, s, 3H;δ 1.95, m, 1H; δ 1.5-1.8, m, 5H; δ 1.5, s, 3H, 1.25, m, 2H; δ 0.95, m,3H; δ 0.85, m, 3H. ES_LCMS (m/e) 309.17.

The following compounds were prepared using similar methods:

Obs. # Structure MW m/e 971

308 309 972

308 309 973

310 311 974

322 323 975

324 325 976

334 335 977

336 337 978

348 349 979

348 349 980

0 351 981

350 351 982

350 351 983

360 361 984

360 361 985

362 363 986

362 363 987

364 365 988

364 365 989

364 365 990

370 371 991

370 371 992

376 377 993

376 377 994

376 377 995

378 379 996

378 379 997

378 379 998

378 379 999

379 380 1000

384 385 1001

384 385 1002

384 385 1003

386 387 1004

388 389 1005

389 390 1006

390 391 1007

390 391 1008

390 391 1009

390 391 1010

390 391 1011

390 391 1012

390 391 1013

390 391 1014

390 391 1015

392 393 1016

392 393 1017

392 393 1018

394 395 1019

398 399 1020

398 399 1021

398 399 1022

398 399 1023

398 399 1024

400 401 1025

400 401 1026

400 401 1027

400 401 1028

400 401 1029

400 401 1030

400 401 1031

400 401 1032

102 403 1033

402 403 1034

404 405 1035

404 405 1036

404 405 1037

404 405 1038

404 405 1039

404 405 1040

404 405 1041

404 405 1042

409 410 1043

410 411 1044

0 411 1045

410 411 1046

412 413 1047

412 413 1048

412 413 1049

414 415 1050

414 415 1051

414 415 1052

414 415 1053

414 415 1054

414 415 1055

414 415 1056

416 417 1057

416 417 1058

417 418 1059

418 419 1060

418 419 1061

418 419 1062

418 419 1063

418 419 1064

420 421 1065

423 424 1066

424 425 1067

424 425 1068

426 427 1069

426 427 1070

426 427 1071

426 427 1072

426 427 1073

427 428 1074

428 429 1075

428 429 1076

428 429 1077

128 429 1078

428 429 1079

430 431 1080

430 431 1081

430 431 1082

432 433 1083

432 433 1084

432 433 1085

432 433 1086

432 433 1087

432 433 1088

438 439 1089

438 439 1090

438 439 1091

438 439 1092

438 439 1093

440 441 1094

440 441 1095

440 441 1096

440 441 1097

442 443 1098

442 443 1099

442 443 1100

442 443 1101

442 443 1102

444 445 1103

444 445 1104

444 445 1105

446 447 1106

446 447 1107

446 447 1108

449 450 1109

451 452 1110

452 453 1111

452 453 1112

452 453 1113

456 457 1114

456 457 1115

456 457 1116

458 459 1117

460 461 1118

460 461 1119

460 461 1120

460 461 1121

462 463 1122

462 463 1123

462 463 1124

462 463 1125

462 463 1126

464 465 1127

466 467 1128

466 467 1129

470 471 1130

472 473 1131

474 475 1132

474 475 1133

476 477 1134

476 477 1135

478 479 1136

482 483 1137

482 483 1138

482 483 1139

488 489 1140

490 491 1141

500 501 1142

502 503 1143

502 503 1144

504 505 1145

504 505 1146

504 505 1147

511 512 1148

512 513 1149

512 513 1150

520 521 1151

520 521 1152

520 521 1153

520 521 1154

522 523 1155

522 523 1156

536 537 1157

536 537 1158

536 537 1159

538 539 1160

538 539 1161

540 541 1162

541 542 1163

542 543 1164

546 547 1165

546 547 1166

550 551 1167

550 551 1168

569 570 1169

582 583 1170

582 583 1171

584 585 1172

584 585 1173

594 595 1174

596 597 1175

596 597

Method R

Method R, Step 1:

A solution of R¹ (n=1, p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu) (0.010 g) inacetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into amicrotiter plate well followed by addition of 0.12 ml of 0.5Mphenylisocyanate solution in dichloroethane. The well was sealed and theplate shaken for 20 h before the mixture was filtered and the solidwashed with acetonitrile (0.5 ml). The combined solution was treatedwith Trisamine resin (0.050 g, 6 eq., 4.23 mmol/g) and Isocyanate resin(0.067 g, 3 eq., 1.53 mmol/g) and the mixture was shaken for 18 h. Themixture was filtered and the solution was evaporated to give R² (n=1,p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph).

Method R, Step 2:

Procedure similar to Method Q, step 6 was used for the transformation ofR2 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph) to R³ (n=1, p=2,m=1, R²═H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph)

The following compounds were prepared using similar methods:

Obs. # Structure MW m/e 1176

309 310 1177

309 310 1178

311 312 1179

325 326 1180

337 338 1181

346 347 1182

351 352 1183

351 352 1184

351 352 1185

365 366 1186

365 366 1187

365 366 1188

367 368 1189

377 378 1190

381 382 1191

385 386 1192

391 392 1193

393 394 1194

395 396 1195

399 400 1196

399 400 1197

399 400 1198

399 400 1199

399 400 1200

401 402 1201

403 404 1202

403 404 1203

407 408 1204

407 408 1205

410 411 1206

410 411 1207

413 414 1208

413 414 1209

415 416 1210

415 416 1211

415 416 1212

415 416 1213

417 418 1214

419 420 1215

419 420 1216

419 420 1217

421 422 1218

421 422 1219

425 426 1220

427 428 1221

427 428 1222

429 430 1223

429 430 1224

431 432 1225

431 432 1226

433 434 1227

435 436 1228

441 442 1229

441 442 1230

441 442 1231

445 446 1232

449 450 1233

453 454 1234

453 454 1235

453 454 1236

453 454 1237

453 454 1238

455 456 1239

455 456 1240

457 458 1241

461 462 1242

463 464 1243

467 468 1244

467 468 1245

471 472 1246

475 476 1247

477 478 1248

477 478 1249

487 488 1250

487 488 1251

487 488 1252

491 492

Method S

Method S, Step 1:

A solution of S1 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=iBu) (0.010 g) inacetonitrile (0.85 mL) and dichloroethane (0.15 mL) was put into amicrotiter plate followed by addition of DIPEA-MP resin (0.030 g, 4 eq)and phenylsulfonyl chloride in dioxane (1M, 45 μL, 0.045 mmol. The wellwas capped and shaken for 18 h before it was filtered and residue washedwith acetonitrile (0.5 mL). The combined solution was treated withTrisamine resin (0.040 g, 6 eq., 4.23 mmol/g) and Isocyanate resin(0.060 g, 3 equiv., 1.53 mmol/g) and shaken for 18 h before the mixturewas filtered and the solvent removed to give S2 (n=1, p=2, m=1, R²═H,R³=Me; R⁴=iBu and R¹⁵=Ph).

Method S, Step 2:

Procedure similar to Method Q, step 6 was used for the transformation ofS2 to S3 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph).

The following compounds were prepared using similar methods:

Obs. # Structure MW m/e 1253

344 345 1254

344 345 1255

358 359 1256

358 359 1257

360 361 1258

372 373 1259

372 373 1260

386 387 1261

406 407 1262

406 407 1263

406 407 1264

412 413 1265

416 417 1266

420 421 1267

420 421 1268

420 421 1269

420 421 1270

420 421 1271

420 421 1272

424 425 1273

424 425 1274

424 425 1275

431 432 1276

432 433 1277

434 435 1278

434 435 1279

436 437 1280

436 437 1281

438 439 1282

440 441 1283

440 441 1284

440 441 1285

442 443 1286

442 443 1287

442 443 1288

442 443 1289

442 443 1290

446 447 1291

448 449 1292

448 449 1293

448 449 1294

454 455 1295

456 457 1296

456 457 1297

458 459 1298

458 459 1299

458 459 1300

462 463 1301

464 465 1302

466 467 1303

466 467 1304

466 467 1305

466 467 1306

470 471 1307

474 475 1308

474 475 1309

474 475 1310

474 475 1311

474 475 1312

474 475 1313

474 475 1314

474 475 1315

474 475 1316

474 475 1317

476 477 1318

480 481 1319

482 483 1320

484 485 1321

484 485 1322

488 489 1323

490 491 1324

490 491 1325

492 493 1326

498 499 1327

508 509 1328

508 509 1329

508 509 1330

508 509 1331

542 543 1332

557 558

Method T

Method T, Step 1:

To a microtiter plate well containing 1 ml solution of T1 (n=1, p=2,m=1, R²═H, R³=Me; R⁴=iBu) in DCM (0.010 g) and R¹⁵C(O)R¹⁶ (5 equiv,R¹⁵═H, R¹⁶=Ph) was added Sodium cyanoborohydride in dichloroethane (14.3mg/mL, 2 equiv.). The well was capped and shaken for 20 h before MP-TsOHResin (100 mg, 1.29 mmol/g) was added to the well followed by additionalMP-TsOH resin (50 mg) after 2 h. After the mixture was shaken foranother 1 h, the mixture was filtered and the resin washed withdichloroethane (1 mL) (3×), then MeOH (1 mL) (2×). The resin was treatedwith 7N ammonia in MeOH (1 mL) for 30 min (2×) followed by filtrationand evaporation of solvent to give T2 (n=1, p=2, m=1, R²═H, R³=Me;R⁴=^(i)Bu and R¹⁵=Ph and R¹⁶═H).

Method T, Step 2:

Procedure similar to Method Q, step 6 was used for the transformation ofT2 (n=1, p=2, m=1, R²═H, R³=Me; R⁴=iBu and R¹⁵=Ph and R¹⁶═H) to T3 (n=1,p=2, m=1, R²═H, R³=Me; R⁴=^(i)Bu and R¹⁵=Ph and R¹⁶═H).

The following compounds were prepared using similar methods:

Obs. # Structure MW m/e 1333

348 349 1334

350 351 1335

350 351 1336

356 357 1337

362 363 1338

370 371 1339

384 385 1340

384 385 1341

400 401 1342

446 447 1343

448 449

Method U

Alternatively, similar synthetic method can be used for the generationof other types of compounds. i.e.

In a microwave vial was charged U1 (R²═H; R³=i-Bu, R⁴=Me) (0.025 g) intoluene (4 mL), potassium carbonate (0.035 g), Pd(dppf)Cl₂ (0.020 g).water (0.02 mL) and R²¹B(OH)₂ (R²¹=m-Methoxyphenyl) (3 eq.) were placed.The vial was placed in a microwave for 10 min. at 150° C. The reactionmixture was diluted with dichloromethane and extracted with 2.5N NaOH.The dried (MgSO₄) dichloromethane solution was concentrated in vacuo togive a brown residue which was purified via a RP Prep LCMS system togive product U2 (R²═H; R³=^(i)Bu: R⁴=Me; R²¹=m-methoxyphenyl).

The following compounds were prepared using similar methods:

Obs. # Structure MW m/e 1344

279 280 1345

285 286 1346

293 294 1347

299 300 1348

299 300 1349

304 305 1350

309 310 1351

313 314 1352

318 319 1353

323 324 1354

323 324 1355

323 324 1356

329 330 1357

335 336 1358

335 336 1359

337 338 1360

343 344 1361

347 348 1362

347 348 1363

347 348 1364

347 348 1365

347 348 1366

349 350 1367

349 350 1368

350 351 1369

351 352 1370

352 353 1371

357 358 1372

359 360 1373

360 361 1374

360 361 1375

360 361 1376

360 361 1377

360 361 1378

360 361 1379

365 366 1380

365 366 1381

365 366 1382

365 366 1383

366 367 1384

371 372 1385

371 372 1386

371 372 1387

372 373 1388

372 373 1389

375 376 1390

377 378 1391

377 378 1392

377 378 1393

377 378 1394

379 380 1395

379 380 1396

380 381 1397

381 382 1398

383 384 1399

384 385 1400

385 386 1401

385 386 1402

386 387 1403

387 388 1404

389 390 1405

389 390 1406

392 393 1407

395 396 1408

403 404 1409

403 404 1410

405 406 1411

406 407 1412

413 414 1413

419 420 1414

497 498 1415

398 TBD 1416

399 TBD

Method V

Method V, Step 1:

Compound VI (R³═R⁴=Me) (14.76 mmole), EDCl (14.76 mmole), HOAt mmole),and DIEA (14.76 mmole) were mixed with 36 ml DCM. This mixture wasstirred at RT for 15 min before 3-chlorobenzylamine was added. After thereaction solution was stirred at RT overnight, it was washed with sodiumcarbonate (3×), water, 1N HCl (4×), and aq sodium bicarbonate and driedover anhydrous sodium sulfate. The solvent was evaporated and theresidue was purified on flash column to give the amide product V2(R¹=3-chlorobenzyl; R³═R⁴=Me).

Method V, Step 2:

Compound V2 (R¹=3-chlorobenzyl; R³═R⁴=Me) (8.33 mmole) was dissolved in35 ml anhydrous DCM, and cooled to 0-5° C. Thiophosgene (9.16 mmole) in10 ml DCM was added dropwise under N₂ followed by addition of DIEA(11.96 mmole). The solution was stirred in ice bath for 0.5 h before thereaction mixture was washed with saturated sodium bicarbonate (3×),brine, and dried over anhydrous sodium sulfate. The solvent wasevaporated and residue purified on flash column usingethylacetate/hexane to give the thiohydantoin V3 (R¹=3-chlorobenzyl;R³═R⁴=Me).

Method V, Step 3:

The thiohydantoin V3 (R¹=3-chlorobenzyl; R³═R⁴=Me) was treated witht-butyl hydroperoxide and ammonium hydroxide in MeOH at RT for 48 h togive compound V4 (R¹=3-chlorobenzyl; R²═H; R³═R⁴=Me).

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 1417

251 252 1418

265 266 1419

293 294 1420

307 308 1421

357 358 1422

371 372

Method W

Compound W1 obtained using method A (n=1, R²=m-Cl-Bn, R³=Me) was zed toW2 (n=1, R²=m-Cl-Bn, R³=Me) using two equivalent of LiOH in MeOH.

The following compounds were synthesized in similar fashion:

Obs. # Structure MW m/e 1423

295 296 1424

311 312 1425

325 326 1426

411 412 1427

425 426

Method X

(In the scheme, -Z-NH—C(O)—N(R¹⁶)(R¹⁷)— is equivalent to R¹ substitutedby R²¹, or R¹ Substituted by alkyl-R²², wherein R²¹ and R²² are—NH—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ is H, and wherein Z is optionallysubstituted alkylene-arylene, alkylene-arylene-alkylene,alkylene-heteroarylene, alkylene-heteroarylene-alkylene,alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene,alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene,arylene, heteroarylene, cycloalkylene or heterocycloalkylene)

Method X, Step1:

To a mixture of the amine X1 obtained using method L (R³=Me; R⁴=^(i)-Bu;Z=para-(CH₂)C₆H₄(CH₂)—) (10 mg) in DCM and sat. NaHCO₃ (1:1 by volume)was added triphosgene (0.33 eq) at r.t. The solution was stirredvigorously for 40 minutes before the organic layer was separated anddried over anhydrous Na₂SO₄. The organic solution was evaporated to givecompound X2 (R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—).

Method X, Step 2:

Compound X3 (R¹⁵═H; R¹⁶=cyclopropylmethyl; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—) was prepared from X2 (R³=Me; R⁴=i-Bu;Z=para-(CH₂)C₆H₄(CH₂)—) using method similar to method M, step 1.

Method X, Step 3:

Compound X4 (R¹⁶═H; R¹⁷=cyclopropylmethyl; R²═H; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—) was prepared from X3 (R¹⁶═H;R¹⁷=cyclopropylmethyl; R²═H; R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—)using method similar to method A Step 3. NMR (CD₃OD): δ 7.25, s, 4H; δ4.8, m, 2H; δ 4.25, s, 2H; δ 2.9, m, 2H; δ 1.68, m, 2H; δ 1.44, m, 1H; δ1.36, s, 3H; δ 0.9, m, 1H, δ 0.82, m, 3H, δ 0.66, m, 3H, δ 0.4, m, 2H; δ0.12, m, 2H. ES_LCMS (m/e) 386.1.

The following compounds were prepared using a similar method.

Obs. # Structure MW m/e 1428

385 386 1429

401 402 1430

401 402 1431

415 416 1432

427 428 1433

435 436 1434

435 436 1435

443 444 1436

449 450 1437

463 464 1438

471 472 1439

485 486 1440

496 497 1441

504 505 1442

513 514 1443

518 519 1444

518 519 1445

524 525 1446

524 525 1447

526 527 1448

532 533 1449

533 534 1450

537 538 1451

537 538 1452

545 546 1453

559 560 1454

570 571 1455

572 573 1456

598 599

Method Y

(In the scheme,

is equivalent to R¹ substituted by R²¹, or R¹ Substituted by alkyl-R²²,wherein R²¹ and R²² are —N(R¹⁵)—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ and R¹⁶ form aring as defined above, and wherein Z is optionally substitutedalkylene-arylene, alkylene-arylene-alkylene, alkylene-heteroarylene,alkylene-heteroarylene-alkylene, alkylene-cycloalkylene,alkylene-cycloalkylene-alkylene, alkylene-heterocycloalkylene,alkylene-heterocycloalkylene-alkylene, arylene, heteroarylene,cycloalkylene or heterocycloalkylene)

Method Y, Step 1:

The reaction mixture of compound Y1 obtained from Method L (R³=Me;R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—) (0.1639 mmole), Y2 (R²³═H; R²³═Pr)(0.1967 mmole), PS-EDC resin (0.4917 mmole) and HOBT (0.2459 mmole) in3.5 ml of mixture of THF, MeCN and DMF (1:1:0.3) was shaken overnight atRT before 6 eq of PS-trisamine resin 3 eq of PS-isocyanate resin wereadded. After 6 hrs the reaction mixture was filtered and the resin waswashed with THF, DCM and MeOH. The combined filtrate was evaporated andthe crude was treated with 40% TFA in DCM for 40 min before the solventwas evaporated and residue purified on RP HPLC system to give product Y3(R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—, R²³═H; R²³═Pr).

Method Y, Step 2:

The reaction solution of Y3 (R³=Me; R⁴=i-Bu; Z=para-(CH₂)C₆H₄(CH₂)—,R²³═H; R²³═Pr) (0.030 mmole), carbonyl diimidazole (0.032 mmole), andDIEA (0.09 mmole) in 0.5 ml DCM was shaken overweekend at RT. The crudewas then purified on reverse column to give the thiohydantoin productwhich was converted into Y4 (R²═H; R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—, R²³═H; R²³═Pr).

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 1457

413 414 1458

413 414 1459

427 428

Method Z

(In the scheme, —Z-—NH—C(O)—N(R¹⁶)(R¹⁷)— is equivalent to R¹ substitutedby R²¹, or R¹ Substituted by alkyl-R²², wherein R²¹ and R²² are—N(R¹⁵)—C(O)—N(R¹⁶)(R¹⁷) and R¹⁵ is H, and wherein Z is optionallysubstituted alkylene-arylene, alkylene-arylene-alkylene,alkylene-heteroarylene, alkylene-heteroarylene-alkylene,alkylene-cycloalkylene, alkylene-cycloalkylene-alkylene,alkylene-heterocycloalkylene, alkylene-heterocycloalkylene-alkylene,arylene, heteroarylene, cycloalkylene or heterocycloalkylene)

Method Z, Step 1:

To the solution of the Phoxime™ resin (1.23 mmol/g) in DCM was added theamine Z1 obtained from method L (R³=Me; R⁴=^(i)Bu;Z=para-CH₂)C₆H₄(CH₂)—) (2 eq). The mixture was shaken overnight beforethe resin was filtered and washed with DCM, MeOH, THF (3 cycles), thenDCM (×2), dried in vacuum to get resin Z2 (R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—).

Method Z, Step 2:

To the resin Z2 (R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—), swelled inDCM, in toluene was added N-methylbenzylamine (4 eq). The mixture washeated at 80-90° C. overnight before MP-TSOH resin (1.3 mmol/g, 12 eq)was added. The mixture was shaken for 1.5 hours, the solution wasfiltered and the resin washed with DCM and MeOH. The combined organicsolution was concentrated in vacuo to get Z3 (R³=Me; R⁴=^(i)Bu;Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me; R¹⁷=Bn).

Method Z, Step 3:

Compound Z4 (R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me; R¹⁷=Bn)was generated from Z3 (R³=Me; R⁴=^(i)Bu; Z=para-(CH₂)C₆H₄(CH₂)—; R¹⁶=Me;R¹⁷=Bn) using method similar to Method A step 3.

The following compounds were prepared using similar method.

Obs. # Structure MW m/e 1460

457 458 1461

469 470 1462

471 472 1463

471 472 1464

483 484 1465

485 486 1466

485 486 1467

495 496 1468

499 500 1469

501 502 1470

507 508 1471

509 510 1472

517 518 1473

517 518 1488

364 365 1489

377 377 1490

513 514 1474

531 532 1475

533 534 1476

533 534 1477

538 539 1478

545 546 1479

547 548 1480

547 548 1481

547 548 1482

551 552 1483

568 569 1484

571 572 1485

593 594 1486

596 597 1487

607 608

Method AA

8,11-Dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (AA2)(18 mg) was reacted with AA1, obtained from method Q, anddiisopropylethylamine (14 uL) in acetonitrile (2.5 mL). The resultingmixture was heated at 65° C. for 18 h. The reaction mixture was placedon a preparative silica gel plate and eluted with hexane:ethyl acetate3:1 to give the desired product which was treated with 40% TFA.Evaporation of the solvent followed by purification afforded compoundAA3.

The following compounds were prepared by similar methods:

Obs. # Structure MW m/e 187

491 492 188

493 494

Method AB

Method AB, Step 1:

To a solution of (R)-(+)-2-methyl-2-propane sulfinamide (1.0g, 8.3 mmol,1 eq) and AB1 (R⁶=Ph, R⁷=n-Bu) (3 mL, 9.1 mmol, 1.1 eq) in anhydrous THF(30 mL) at room temperature was added Ti(OEt)₄ (7 mL, 17 mmol, 2 eq).The mixture was heated at 70° C. for 24 h. After cooling to roomtemperature, the mixture was poured into 30 mL of brine under vigourousstirring. The resulting suspension was filtered through a pad of Celiteand the solid was washed with EtOAc (2×20 mL). The filtrate was washedwith brine (30 mL), dried (Na₂SO₄), and concentrated in vacuo. Theresidue was chromatographed on silica by eluting with hexane/Et₂O (5:1)to give 1.9g (85%) of(R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide. ¹HNMR (CDCl₃,300 MHz): δ 7.91 (m, 2H), 7.52-7.37 (m, 3H), 3.27 (m, 1H), 3.15 (m, 1H),1.73-1.61 (m, 2H), 1.47-1.38 (m, 2H), 1.31 (s, 9H), 0.95 (m, 3H). MS(ESI): MH⁺=265.9. HPLC t_(R)=7.24, 7.58 min (E/Z=5.5:1).

To a solution of methyl acetate (0.6 mL, 6.9 mmol, 2 eq) in THF (5 mL),LDA (2M in heptane/THF, 3.4 mL, 6.9 mmol, 2 eq) was added dropwise via asyringe at −78° C. After stirring at −78° C. for 30 min, a solution ofClTi(Oi-Pr)₃ (1.8 mL, 7.6 mmol, 2.2 eq) in THF (5 mL) was addeddropwise. After stirring for another 30 min, a solution of(R)-2-methyl-N-(1-phenylpentylidene)propane-2-sulfinamide (0.9g, 3.4mmol, 1 eq) in THF (2 mL) was added dropwise via a syringe. The mixturewas stirred at −78° C. for 3 h and TLC showed no starting material left.A saturated aqueous solution of NH₄Cl (10 eq) was added and thesuspension was warmed to room temperature. The mixture was diluted withH₂O (50 mL) and stirred for 10 min. The mixture was then partitionedbetween H₂O (50 mL) and EtOAc (50 mL). The organic layer was separatedand the aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated togive 1.1g of a brown oil. Chromatography on silica gel using 50%EtOAc/hexanes as eluent gave 0.8g (76%) of methyl3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate as a yellowoil. ¹HNMR (CDCl₃, 300 MHz): δ 7.15-7.07 (m, 5H), 3.35 (s, 1H), 3.19(dd, J=16, 5.6 Hz, 1H), 3.01 (dd, J=15.8, 5.5 Hz, 1H), 2.07 (m, 2H),1.71 (m, 2H), 1.35-1.26 (m, 4H), 1.17 (s, 9H), 0.89 (m, 3H). MS (ESI):MH⁺=339.9. HPLC t_(R)=7.50, 7.6 min (E/Z=1.5:1)

To a solution of methyl3-((R)-2-methylpropan-2-ylsulfinamido)-3-phenylheptanoate (0.4g, 1.1mmol) in 12 mL of MeOH was added 16 mL of 4N HCl/dioxane. After stirringfor 30 min, the volatiles were removed in vacuo. The residue wasre-dissolved in MeOH (6 mL), stirred for 5 min, and evaporated again toafford 0.30g (97%) of AB2 (R⁶=Ph, R⁷=n-Bu) as a yellow solid. ¹HNMR(CDCl₃, 300 MHz): δ9.01 (br s, 2H), 7.37-7.12 (m, 5H), 3.64 (m, 1H),3.54 (s, 3H), 3.31 (m, 1H), 2.09 (m, 2H), 1.8 (m, 2H), 1.1 (m, 4H), 1.07(s, 9H), 0.7 (m, 3H). MS (ESI): MH⁺=235.9. HPLC t_(R)=4.72 min.

Method AB, Step 2:

Treatment of compound AB2 (R⁶=Ph, R⁷=n-butyl) with thiophosgene inCH₂Cl₂ in the presence of aqueous NaHCO₃ at 0° C. generatesisothiocyanate AB3 (R⁶=Ph, R⁷=n-butyl) which was converted into finalproduct using method similar to Method A Step 2 and Method A Step 3 togive product AB5 (R⁶=Ph, R⁷=n-butyl, R¹=Me). ¹HNMR (CDCl₃, 300 MHz): δ10.4 (br s, 1H), 7.25-7.11 (m, 5H), 3.23 (dd, J=16, 5.6 Hz, 1H), 3.03(s, 3H), 2.8 (dd, J=15.8, 5.5 Hz, 1H), 2.49 (s, 1H), 1.78 (m, 2H),1.1-1.0 (m, 4H), 0.99 (m, 3H). MS (ESI): MH⁺=260.2. HPLC t_(R)=5.09 min.

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 189

239 240 190

253 254 191

259 260 192

333 334 193

333 334 194

349 350 195

443 444 196

463 464 197

537 538 198

537 538 199

295 296 200

295 296

Method AC

The synthesis was adapted from a procedure by Hull, R. et al, J. Chem.Soc. 1963, 6028-6033. Thus, to a solution of AC2 (R¹=Benzyl) (0.72 g,5.9 mmol) in AC1 (R⁴=Me, R³=Me) (1.4 mL) was added a 50% aqueoussolution of cyanamide (0.31 mL, 8.0 mmol). The reaction was heated withstirring at reflux (˜40° C.) for 0.5 h, then cooled to 25° C. andstirred for an additional 16 h. The volatiles were removed in vacuo andthe residue was partitioned between ether and H₂O. The organic layer wasdried over Na₂SO₄, filtered and the volatiles were removed in vacuo. Theresidue was purified by column chromatography using 5-10% CH₃OH/CH₂Cl₂as eluent followed by reverse phase preparative HPLC to give 0.15 g(8.0%) of AC3 (R¹=benzyl, R⁴=Me and R³=Me) as a white solid. ¹H NMR(CH₃OH, 300 MHz): δ 7.35-7.33 (m, 5H), 4.71 (s, 2H), 1.46 (s, 6H); ¹³CNMR (CDCl₃, 75 MHz) δ 157.8, 135.6, 129.1, 128.5, 127.9, 104.2, 59.6,28.8. MS (ESI) m/e 206.1 (M+H)⁺.

# Structure MW Obs. m/e 201

205 206

Method AD

Method AD, Step 1:

AD2 (R³=Ph, R⁴=^(t)Butyl) was prepared from AD1 using method similar toMethod AB, step 2.

Method AD, Step 2:

The synthesis was adapted from a procedure by Hussein, A. Q. et al,Chem. Ber. 1979, 112, 1948-1955. Thus, to a mixture of AD2 (R³=Ph,R⁴=tert-Butyl) (0.56 g, 2.7 mmol) and boiling chips in CCl₄ (25 mL) wasadded N-bromosuccinimide (0.49 g, 2.7 mmol). The mixture was irradiatedwith a 200 watt light source for 1 h. The reaction was cooled, the solidfiltered off and the volatiles were removed in vacuo. Chromatography onsilica gel by eluting with 5% EtOAc/hexane gave 0.57 g (73%) of1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene as a beigepowder. ¹H NMR (CDCl₃, 300 MHz): δ 7.63-7.61 (m, 2H), 7.37-7.26 (m, 3H),1.17 (s, 9H); ¹³C NMR (CDCl₃, 75 MHz): δ 139.1, 129.0, 128.9, 128.6,127.5, 91.2, 45.6, 26.6. MS (ESI) m/e 284.9 (M+H)⁺.

To a solution of 1-(1-bromo-1-isothiocyanato-2,2-dimethylpropyl)benzene(0.13 g, 0.47 mmol) and the hydrochloride salt of N-methylhydroxylamine(0.047 g, 0.57 mmol) in THF (3 mL) was added triethylamine (0.18 mL,1.32 mmol). The mixture was stirred at 25° C. for 16 h, filtered and thevolatiles were removed in vacuo. The residue was purified by columnchromatography using CH₃OH/CH₂Cl₂ as eluent to give 0.050 g (42%) of AD3(R³=Ph, R⁴=tert-Butyl) as a glassy solid. ¹H NMR (CDCl₃, 300 MHz): δ7.35-7.26 (m, 5H), 3.38 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 251.1 (M+H)⁺.

Method AD, Step 3:

To a solution of AD3 (R³=Ph, R⁴=tert-Butyl) (0.065 g, 0.26 mmol) inCH₃OH (5 mL) at 0° C. was added a solution of aqueous ammonia (2 mL)followed by a 70% aqueous solution of t-butylhydroperoxide (2 mL). Thereaction was allowed to warm to 25° C. and stirred for 16 h, Thevolatiles were removed and the residue was purified by reverse phaseHPLC to give 2.0 mg (2.2%) of AD4 (R³=Ph, R⁴=tert-Butyl) as a colorlessoil. ¹H NMR (CDCl₃, 300 MHz) δ 7.47-7.43 (m, 2H), 7.39-7.35 (m, 3H),3.23 (s, 3H), 1.0 (s, 9H); MS (ESI) m/e 234.2 (M+H)⁺.

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 202

213 214 203

233 234 204

309 310

Method AE

Method AE, Step 1:

TBDMS-Cl (5.3 g, 35.19 mmole) and imidazole (2.4 g, 35.19 mmole) wereadded to a suspension of H2 (R¹=Me, R³=cyclohexylmethyl) (8.2 g, 31.99mmole) in 220 ml DCM. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was filtered, and thefiltrate was diluted with 1200 ml EtOAc. The organic phase was washedwith saturated NaHCO₃ 3× and brine 3×, and dried over anhydrous Na₂SO₄to give 12g of AE2 (R¹=Me, R³=cyclohexylmethyl), which was used for nextstep without further purification.

Method AE, Step 2:

AE2 (R¹=Me, R³=cyclohexylmethyl; 12 grams crude) was converted toiminohydantoin using conditions similar to Method A Step 3, which wassubsequently treated with 75% TFA in DCM at room temperature for 24 hrs.The solvent was evaporated in vacuo to give 13.6g of a product that wasreacted with Boc anhydride to give 5.8g AE3 (R¹=Me, R³=cyclohexylmethyl)after column purification.

Method AE, Step 3:

AE4 (R¹=Me, R³=cyclohexylmethyl) (8.2g) was obtained from AE3 (5.8g)according to the step 4 of the method H.

Method AE, Step 4:

To a solution of AE4 (R¹=Me, R³=cyclohexylmethyl) ((3.95g, 8.38 mmol) inanhydrous THF (98 mL) was added diisopropylethylamine (7 mL, 40 mmol).The reaction was stirred under N₂ (gas) at room temperature. After 5.5h, the reaction was concentrated and the crude material was purified viaflash chromatography eluting with a gradient of 0 to 75% ethyl acetatein hexane to afford AE5 (R¹=Me, R³=cyclohexylmethyl) (2.48 g, 92%).

Method AE, Step 4:

To a solution of R¹⁵OH(R¹⁵=cyclobutyl) (10 μl) and HBF₄ (1 equiv) inanhydrous methylene chloride (0.5 mL) was added a solution of AE5(R¹=Me, R³=cyclohexylmethyl) (20 mg, 0.062 mmol) in methylene chloride(0.5 mL). The reaction was agitated overnight at rt. Trifluoroaceticacid (1 mL) was added to the reaction mixture and the solution wasagitated for 1 h at rt. The reaction was concentrated and the crudematerial was purified via reverse phase preparative HPLC/MS eluting witha 7 min gradient of 5 to 95% CH₃CN in H₂O with 0.1% formic acid toafford AE5 (R¹=Me, R³=cyclohexylmethyl, R¹⁵=cyclobutyl).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 205

267 268 206

293 294 207

295 296 208

295 296 209

295 296 210

295 296 211

305 306 212

307 308 213

307 308 214

309 310 215

309 310 216

309 310 217

309 310 218

321 322 219

321 322 220

321 322 221

322 323 222

329 330 223

333 334 224

335 336 225

335 336 226

335 336 227

335 336 228

335 336 229

335 336 230

335 336 231

335 336 232

335 336 233

337 338 234

337 338 235

349 350 236

349 350 237

349 350 238

349 350 239

353 354 240

361 362 241

363 364 242

363 364 243

363 364 244

389 390 245

321 NA

Method AF

To a solution of tBuOK (9.5 mg, 0.0848 mmole) in 0.5 ml anhydrous THFwas added ArOH (Ar=m-Chlorophenyl) (13 μl, 0.1273 mmole) in 0.5 mlanhydrous THF followed by addition of AE4 (R¹=Me, R³=cyclohexylmethyl)(20 mg, 0.0424 mmole) in 0.5 ml anhydrous THF. The reaction mixture wasstirred at room temperature for 2 days before it was diluted with 1 mlMeCN, treated with 100 mg MP-TsOH resin and 100 mg Amberlyst A26 resin.The resin was removed by filtration and the filtrate was evaporated downto give a product that was treated with 50% TFA for 1 hr. Afterevaporation of TFA in vacuo, the residue was dissolved in 2 ml MeCN, andtreated with 100 mg MP-TsOH resin. The resin was washed thoroughly withTHF, MeCN and MeOH, and then treated with 2M NH₃ in MeoH to give AF2(R¹=Me, R³=cyclohexylmethyl and R¹⁵=3-chlorophenyl).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 246

316 317 247

316 317 248

316 317 249

329 330 250

329 330 251

329 330 252

330 331 253

331 332 254

331 332 255

333 334 256

333 334 257

333 334 258

333 334 259

333 334 260

340 341 261

340 341 262

340 341 263

343 344 264

343 344 265

343 344 266

343 344 267

344 345 268

344 345 269

345 346 270

345 346 271

345 346 272

345 346 273

347 348 274

347 348 275

349 350 276

349 350 277

349 350 278

349 350 279

351 352 280

351 352 281

351 352 282

351 352 283

351 352 284

351 352 285

351 352 286

351 352 287

355 356 288

355 356 289

357 358 290

357 358 291

357 358 292

357 358 293

358 359 294

358 359 295

358 359 296

358 359 297

359 360 298

359 360 299

359 360 300

359 360 301

359 360 302

360 361 303

360 361 304

360 361 305

363 364 306

363 364 307

363 364 308

363 364 309

365 366 310

365 366 311

366 367 312

366 367 313

366 367 314

366 367 315

366 367 316

366 367 317

366 367 318

367 368 319

367 368 320

367 368 321

369 370 322

371 372 323

371 372 324

371 372 325

372 373 326

372 373 327

372 373 328

372 373 329

373 374 330

373 374 331

375 376 332

375 376 333

375 376 334

377 378 335

377 378 336

377 378 337

383 384 338

383 384 339

383 384 340

383 384 341

383 384 342

383 384 343

383 384 344

383 384 345

383 384 346

383 384 347

385 386 348

385 386 349

386 387 350

387 388 351

387 388 352

393 394 353

393 394 354

393 394 355

393 394 356

399 400 357

399 400 358

400 401 359

400 401 360

400 401 361

401 402 362

401 402 363

401 402 364

405 406 365

411 412 366

414 415 367

417 418 368

417 418 369

421 422 370

434 435 371

451 452

Method AG

Method AG, Step 1:

R²¹—H(R²¹=PhS—) (33 μl, 0.318 mmole) was treated with NaH (10.2 mg, 60%in mineral oil) in 0.5 ml anhydrous THF. A solution of AE4 (R¹=Me,R³=Cyclohexylmethyl) (20 mg, 0.0424 mmol) in 0.5 ml anhydrous THF wasadded. The reaction mixture was stirred at room temperature overnightbefore it was partitioned between ether and saturated NaHCO₃ watersolution. The aqueous phase was extracted with ether 2 times. Thecombined organic phase was washed with brine 2 times, and dried overanhydrous NaSO₄. The crude was purified on flash column withEtOAc/hexane to give 9 mg of AG1 (R²¹=PhS—, R¹=Me, R³=cyclohexylmethyl)(49.2% yield).

Method AG, Step 2:

AG1 (R²=PhS—, R¹=Me, R³=cyclohexylmethyl) was treated with 50% TFAaccording to the Step 6 of the method H to give AG2 (R²¹=PhS—, R¹=Me,R³=cyclohexylmethyl).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 372

315 316 373

331 332 374

337 338

Method AH

Method AH, Step 1:

Benzophenone imine (3.27 g, 18.04 mmole) was added to a suspension ofAH1 (R³=cyclohexylmethyl) (4 g, 18.04 mmole) in 65 ml DCM. The reactionmixture was stirred at room temperature overnight under N₂ before thesolid was filtered, and the solvent was evaporated. The residue wasdissolved in 100 ml ether, washed with water 2× and dried over anhydrousMgSO₄. The crude was purified on flash column to give 5.08 g (80.57%yield) of AH2 (R³=cyclohexylmethyl).

Method AH, Step 2:

A solution of AH2 (R³=cyclohexylmethyl) (1 g, 2.86 mmole) in 12 mlanhydrous THF was added to a suspension of 18-crown-6 (0.76 g, 2.86mmole) and 30% KH in mineral oil (1.16 g, 8.58 mmole) in 4 ml anhydrousTHF under N2. The mixture was cooled in ice-bath and R⁴Br(R⁴=3-pyridylmethyl, as a hydrobromide salt) was then added. Thereaction mixture was stirred in ice-bath for 30 min and at roomtemperature for 2 more hrs before the reaction was quenched with 2 ml ofHOAc/THF/H₂O (0.25:0.75:1). The mixture was diluted with 40 ml EtOAc/H₂O(1:1). The aqueous phase was extracted with EtOAc 3 times. The combinedorganic phase was washed with brine 3 times and dried over anhydrousMgSO4. The crude was purified on flash column to give 0.44 g (35.14%yield) of product which was treated with 1N HCl (2.2 ml, 2.22 mmole) in3 ml ether in ice-bath followed by stirred at r.t. overnight. Theaqueous phase was evaporated and purified on C-18 reverse phase columnto give 0.22 g (66% yield) of AH3 (R⁴=3-pyridylmethyl;R³=cyclohexylmethyl).

Method AI

To a solution of compound AI1 (R¹=Me, R³=n-Bu) (34 mg, 0.105 mmol) inmethanol (1 ml) was added 10% Pd/C (5 mg). The mixture was kept under anH₂ balloon for 1 hr. After filtration of the catalyst, the filtrate wasconcentrated to get crude product. This residue was purified by RP HPLCto get compound AI2 (R¹=Me, R³=n-Bu) (25 mg, 100%). Observed MW (M+H)246.1; exact mass 245.15. ¹H NMR (400 MHz, CD₃OD): δ=7.59 (m, 2H), 7.36(m, 3H), 3.17 (s, 3H), 2.17 (m, 2H), 1.27 (m, 4H), 0.86 (t, 3H, J=7.2Hz).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 375

283 284 376

285 286 377

299 300 378

450 451 379

462 463 380

463 464 381

487 488 382

489 490 383

503 504 384

516 517

Method AJ

To a mixture of compound AJ1 (R¹=Me, R³=n-Bu) (70 mg, 0.165 mmol) andbutylzincbromide (1.32 ml, 0.6 mmol) was added Pd(dppf)Cl₂. The mixturewas degassed, sealed and heated at 55° C. for 1 day. The mixture wasdiluted with CH₂Cl₂ and NH₃/H₂O. The organic layer was separated, dried,concentrated, and purified by RP HPLC to get product which was thentreated with 4N HCl/dioxane for 30 min to give compound AJ2 (R¹=Me,R³=n-Bu) (12 mg, 25%). Observed MW (M+H) 302.1; ¹H NMR (400 MHz, CD₃OD):δ=7.32 (m, 3H), 7.22 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.20 (m, 2H),1.60 (m, 2H), 1.38 (m, 4H), 1.24 (m, 2H), 0.92 (m, 6H).

The following compound was synthesized in a similar fashion:

Obs. # Structure MW m/e 386

518 519 385

301 302

Method AK

To a solution of AK1 (R¹=Me, R³=n-Butyl, R²¹=n-Bu) (9 mg, 0.03 mmol) inmethanol (1 ml) was added 5% Pt/C (5 mg), Rh/C (5 mg) and conc. HCl(0.05 ml). The mixture was kept under H₂ (50 psi) for 2 days. After thefiltration of the catalyst, the filtrate was concentrated to getcompound AK2 (R¹=Me, R³=n-butyl, R²¹=n−Bu) Observed MW (M+H) 308.1. ¹HNMR (CD₃OD): δ=3.16 (s, 3H), 1.80 (m, 6H), 1.26 (m, 16H), 0.88 (m, 6H).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 387

277 278 388

291 292 389

305 306 390

307 308 391

391 392 392

391 392

Method AL

Method AL, Step 1:

To a solution of compound AL1 (R³=n-Bu) (418 mg, 1.39 mmol) in methanol(8 ml) was added PtO₂ (40 mg) and conc. HCl (0.4 ml). The mixture washydrogenated (50 psi) for 1 day. After filtration of the catalyst, thefiltrate was concentrated. The crude residue was basified to pH=11-12 by1N NaOH. This mixture was extracted with ethyl acetate. The organiclayer was separated, dried and concentrated to get compound AL2(R³=n-Bu) (316 mg, 100%).

Method AL, Step 2:

To a solution of compound AL2 (R³=n-Bu) (300 mg, 1.32 mmol) indichloromethane (6 ml) was added (BOC)₂O (316 mg, 1.45 mmol). Themixture was stirred at RT for 1.5 hr. It was diluted with water anddichloromethane. The organic layer was separated, dried and concentratedto get compound AL3 (R³=n-Bu) (464 mg, 100%).

Method AM

Method AM, Step 1:

Compound AM1 (R¹=Me, R³=n-Butyl) was treated with 4N HCl in dioxane for2 hr. The mixture was concentrated to get compound AM2 as an HCl salt(R¹=Me, R³=n-Butyl). Observed MW (M+H) 470.1; ¹H NMR (CD₃OD): δ=7.28 (m,2H), 6.96 (m, 3H), 4.80 (m, 2H), 4.56 (m, 1H), 4.00 (m, 1H), 3.64 (m,4H), 3.37 (m, 2H), 3.12 (m, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.72 (m,1H), 2.38 (m, 1H), 2.12-1.62 (m, 8H), 1.35 (m, 6H), 1.12 (m, 1H), 0.91(m, 3H).

Method AM, Step 2:

To a solution of compound AM2 (R¹=Me, R³=n-Butyl) (32 mg, 0.068 mmol) indichloromethane (1 ml) was added acetyl chloride (5 ul, 0.072 mmol). Themixture was stirred for 2 hr. It was then diluted with CH₂Cl₂ and water.The organic layer was separated, dried, concentrated and purified by RPHPLC to get compound AM3 (R¹=Me, R³=n-Butyl and R¹⁵=Me) Observed MW(M+H) 512.3; ¹H NMR (400 MHz, CDCl₃): δ=7.27 (m, 2H), 6.98 (m, 1H), 6.92(m, 2H), 4.65 (s, 2H), 4.50 (m, 2H), 3.98 (m, 1H), 3.70 (m, 1H), 3.41(m, 2H), 2.98 (m, 2H), 2.62 (m, 1H), 2.50 (m, 1H), 2.47 (m, 1H), 2.02(m, 5H), 1.75 (m, 6H), 1.26 (m, 7H), 0.84 (m, 3H).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 394

252 253 395

252 253 396

456 457 397

469 470 398

498 499 399

511 512

Method AN

To a solution of compound AN2(R¹=4-N-(α-phenoxyacetyl)piperidinylmethyl, R³=n-Butyl) (28 mg, 0.06mmol) in dichloroethane (2 ml) was added butyraldehyde (5.3 ul, 0.06mmol), triethylamine (8.4 ul, 0.06 mmol) and NaBH(OAc)₃ (18 mg, 0.084mmol). The mixture was stirred overnight. It was then diluted withdichloromethane and water. The organic layer was separated, dried,concentrated and purified by RP HPLC to get AN2(R¹=4-N-(a-phenoxyacetyl)piperidinylmethyl, R³=n-Butyl, R¹⁵=propyl andR¹⁶═H) (5.4 mg, 17%). Observed MW (M+H) 526.1; exact mass 525.37. ¹H NMR(CD₃OD): δ=7.28 (m, 2H), 6.96 (m, 3H), 4.76 (m, 2H), 4.55 (m, 1H), 4.05(m, 1H), 3.77 (m, 1H), 3.61 (m, 3H), 3.50 (m, 1H), 3.11 (m, 4H), 2.85(m, 1H), 2.68 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.95 (m, 2H), 1.73(m, 5H), 1.39 (m, 8H), 1.10 (m, 1H), 0.99 (m, 3H), 0.92 (m, 3H).

The following compound was synthesized using similar method:

Obs. # Structure MW m/e 400

308 309 401

308 309 402

525 526

Method AO

A mixture of copper chloride (2.06 g, 20.8 mmol) and lithium chloride(1.76 g, 41.6 mmol) in 100 ml of THF was cooled down to −78° C. To thismixture, a 2.0M solution of AO1 (R³=n-butyl) (10 ml, 20 mmol) was addedgradually. The reaction was warmed up to −60° C., and AO2 (R⁴=m-Br-Ph)(2.9 ml, 22 mmol) was injected. The mixture was stirred at −60° C. for15 minutes and then quickly warmed up to RT by removing the dry-icebath. The reaction was quenched with water and sat. NaHCO₃. Afteraddition of diethyl ether, a lot of precipitate formed and was filtered.From the biphasic filtrate, the organic layer was separated, dried,concentrated and purified by silica gel chromatography (10%EtOAc/hexane) to get ketone AO3 (R⁴=m-BrPh, R³=n-Bu) (3.93 g, 82%).Observed MW (M+H) 241.1; exact mass 240.01. ¹H NMR (400 MHz, CDCl₃):δ=8.07 (m, 1H), 7.88 (m, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 2.94 (t, 3H,J=7.2 Hz), 1.71 (m, 2H), 1.40 (m, 2H), 0.95 (t, 3H, J=7.6 Hz).

The following ketones were made according to Method 9:

Observed MW Structure (M + H) Exact mass

242.1 241.01

Method AP

Method AP, Step 1:

To a solution of AP1 (R⁴=3-Bromophenyl) (5 g, 25 mmol) indichloromethane (10 ml) were added N,O-dimethylhydroxylaminehydrochloride (2.56 g, 26.25 mmol) and 4-methylmorpholine (2.95 ml,26.25 mmol). EDCl (5.04 g, 26.25 mmol) was then added portionwise. Thereaction mixture was stirred at RT overnight and was then quenched with1N HCl (60 ml). The mixture was extracted with dichloromethane. Theorganic layer was washed with 1N HCl and brine, dried over Na₂SO₄, andconcentrated to give the Weinreb amide AP2 (R⁴=m-Bromophenyl) (5.96 g,98%). Observed MW (M+H) 244.1; exact mass 243.99. ¹H NMR (CDCl₃): δ=7.78(m, 1H), 7.58 (m, 2H), 7.24 (m, 1H), 3.51 (s, 3H), 3.32 (s, 3H). Thismaterial was used in the next step without purification.

Method AP, Step 2:

To a suspension of magnesium turnings (1.19 g, 48.8 mmol) in 30 ml ofTHF was added dropwise a solution of R³Br (R³=cyclohexylethyl) (5.73 ml,36.6 mmol) in 24 ml of THF. After addition of half of the solution ofbromide, several crystals of iodine were added to initiate the reaction.The mixture became cloudy and heat evolved. The rest of the solution ofbromide was added dropwise. The mixture was stirred at RT for 30 minutesand then was cooled to 0° C., and the AP2 (R⁴=m-Bromophenyl) (5.96 g,24.4 mmol) was added. The mixture was stirred at RT for 3 hr and thenquenched with 1N HCl until no residual Mg(0) was left. The phases wasseparated, and the water layer was extracted with ether. The combinedorganic layers were washed with brine, dried, and concentrated. Thecrude was purified by silica chromatography (15% EtOAc/hexane) to getketone AP3 (R⁴=m-Bromophenyl, R³=Cyclohexylethyl) (8.06 g, 100%).Observed MW (M+H) 295.2; exact mass 294.06. ¹H NMR (400 MHz, CDCl₃):δ=8.18 (m, 1H), 7.85 (m, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 2.94 (t, 3H,J=7.2 Hz), 1.70 (m, 9H), 1.63 (m, 4H).

Method AQ

To a −78° C. solution of AQ1 (R⁴=cyclopropyl) (2.55 g, 38.0 mmol) indiethyl ether (100 ml) was added AQ3 (R³=n-Bu) (38 ml, 1.5 M in hexanes,57 mmol). After 45 min, the cooling bath was removed. After 3 h at RT,the reaction was quenched by dropwise addition of water and then dilutedfurther with EtOAc and water. The phases were separated and the aqueouslayer was extracted with EtOAc (2×). The organic portions were combined,washed with brine, dried over MgSO₄, and concentrated. This cruderesidue was subjected to column chromatography (silica gel, 0%→100%CH₂Cl₂/hexanes) to provide the desired ketone AQ4 (R⁴=cyclopropyl,R³=n-Butyl) (2.57 g, 20.4 mmol, 54%). ¹H NMR (CDCl₃) δ 2.52 (t, J=7.2Hz, 2H), 1.90 (m, 1H), 1.57 (m, 2H), 1.30 (m, 2H), 0.98 (m, 2H), 0.89(t, J=7.6 Hz, 3H), 0.83 (m, 2H).

Method AR

Method AR:

Compound B2 (R¹=m-Cl-Phenethyl, R³=Me, R⁴=i-butyl and R⁵=benzyl) wasconverted into AR2 (R¹=m-Cl-Phenethyl, R³=Me, R⁴=i-butyl and R⁵=benzyl)using method A step 3.

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 403

396 397 404

354 NA 405

477 NA 406

460 NA 407

340 NA 408

382 NA 409

446 NA

Method AS

Method AS, Step 1:

To a mixture of AS1 (R³=Ph) (3.94 g) in toluene (10 ml) was addedthionyl chloride (1.61 ml) and the resulting mixture as heated underreflux for 6 h (until HCl evolution ceased). The reaction mixture waskept overnight at rt before it was concentrated in vacuo. Toluene (10ml) was added and the mixture was concentrated in vacuo again. Thereaction mixture was dissolved in CH₂Cl₂, solid sodium bicarbonateadded, filtered and then the CH₂Cl₂ solution was concentrated in vacuoto give AS2 (R³=Ph).

Method AS, Step 2:

To AS2 (R³=Ph) (0.645 g) and AS5 (R⁴=4-chlorophenyl) (0.464 g), and1,3-dimethylimidazolium iodide (0.225 g) in anhydrous THF (20 ml) wasadded 60% sodium hydride in oil (0.132 g). The resulting mixture wasstirred at rt for 18 h. The reaction mixture was concentrated andpartitioned between H₂O and Et₂O. The dried Et₂O solution wasconcentrated in vacuo to give a yellow residue which was placed onpreparative silica gel plates and eluted with CH₂Cl₂ to give AS3 (R³=Ph,R⁴=p-ClPh). (Miyashita, A., Matsuda, H., Hiagaskino, T., Chem. Pharm.Bull., 1992, 40 (10), 2627-2631).

Method AS, Step 3:

Hydrochloric acid (1N, 1.5 ml) was added to AS3 (R³=Ph, R⁴=p-ClPh) inTHF (10 ml) and the resulting solution was stirred at rt for 20 h. Thereaction mixture was concentrated in vacuo and then partitioned betweenCH₂Cl₂ and H₂O. The dried CH₂Cl₂ was concentrated in vacuo to give aresidue which was placed on preparative silica gel plates and elutedwith CH₂Cl₂:hexane 1:1 to afford AS4 (R³=Ph, R⁴=p-ClPh).

Method AS, Step 4:

AS4 (R³=Ph, R⁴=p-ClPh) (0.12 g) and methylguanidine, HCl (AS6, R¹=Me)(0.055 g) were mixed in absolute EtOH (5 ml) with triethylamine (0.2 ml)and then heated under reflux for 20 h. The resulting mixture wasconcentrated and then partitioned between CH₂Cl₂ and H₂O. The driedCH₂Cl₂ was concentrated in vacuo to give a residue which was placed onpreparative silica gel plates and eluted with CH₂Cl₂:MeOH 9:1 to affordAS5 (R³=Ph, R⁴=p-ClPh and R¹=Me).

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 411

265 266 412

265 266 413

271 272 414

271 272 415

279 280 416

295 296 417

295 296 418

299 300 419

299 300 420

309 310 421

325 326 422

343 344 423

343 344 424

421 422 425

482 483 426

512 513 427

560 561

Method AT

Method AT, Step1:

AT1, prepared using a method similar to Method H, Step1, 2 and 3, (n=4,R³═R⁴=n-Bu) (0.146 g) in MeOH (3 ml) and 1N NaOH (0.727 ml) were stirredovernight at rt. The mixture was concentrated and then partitioned inwater (pH ˜3, adjusted using conc. HCl) and EtOAc. The dried EtOAc layerwas concentrated in vacuo to afford AT2 (n=4, R³═R⁴=n-Bu).

Method AT, Step 2

Compound AT2 (n=4, R³═R⁴=n-Bu) (0.012 g) in MeCN (1 ml) was treated withEDC resin (0.12 g, 1.44 mmol/g), HOBT (0.004 g) in THF (1 ml), andn-butylamine (R15=H, R16=n-butyl) (0.007 ml). The reaction was carriedout overnight at rt. before Argonaut PS—NCO resin (0.150 g),PS-polyamine resin (0.120 g) and THF (2 ml) were added and the mixtureshaken for 4 h. The reaction mixture was filtered and resin washed withTHF (2 ml). The combined organic phase was concentrated in vacuo beforethe residue was treated with 1N HCl in MeOH (1 ml) for 4 h followed byevaporation of solvent to give AT3 (n=4, R³═R⁴=n-Bu, R¹⁵═H andR¹⁶=n-Butyl).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 428

324 325 429

325 326 430

338 339 431

339 340 432

366 367 433

368 369 434

380 381 435

382 383 436

400 401 437

406 407 438

414 415 439

414 415 440

420 421 441

428 429 442

444 445 443

458 459

Method AU

A published procedure was adapted (Varga, I.; Nagy, T.; Kovesdi, I.;Benet-Buchholz, J.; Dormab, G.; Urge, L.; Darvas, F. Tetrahedron, 2003,(59) 655-662).

AU1 (R¹⁵═H, R¹⁶═H) (0.300 g), prepared according to procedure describedby Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.,(Vogel's Textbook of Practical Organic Chemistry. 5^(th) ed. Longman:new York, 1989; pp 1034-1035), AU2 (HCl salt, R¹=Me) (0.237 g), 50% KOH(0.305 ml), 30% H₂O₂ (0.115 ml) and EtOH (4.6 ml) were heated in asealed tube for 2 h. Reaction mixture was concentrated and extractedwith CH₂Cl₂. The dried organic solution was concentrated in vacuo togive a residue which was placed on preparative silica gel plates elutingwith CH₂Cl₂:MeOH 9:1 to afford AU3 (R¹⁵═H, R¹⁶═H, R¹=Me).

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 444

265 266 446

280 281 447

285 286 448

285 286 449

309 310 450

309 310

Method AV

Method AV, Step 1:

In a microwave tube, AV1 (R³=Me, R⁴=Bu-i) (0.0012 g) and AV2 (R²²═OPh)(0.0059 ml) in isopropanol (2 ml) was placed in a microwave at 125° C.for 5 min. The reaction mixture was concentrated in vacuo to give AV3(R³=Me, R⁴=i-Bu, R²²═OPh).

Method AV, Step 2:

AV3 (R³=Me, R⁴=i-Bu, R²²═OPh) in CH₂Cl₂ (1 ml) and TFA (1 ml) was shakenfor 2 h and the concentrated in vacuo and purified on Prep LCMS toafford AV4 (R³=Me, R⁴=i-Bu, R²²═OPh).

The following compounds were synthesized in a similar fashion.

Obs. # Structure MW m/e 451

378 379 452

396 397 453

416 417

Method AW

Method similar to Method U was used for this transformation. Thefollowing compounds were generated using similar methods.

The following compounds were synthesized in a similar fashion:

Obs. # Structure MW m/e 454

341 342 455

341 342 456

342 343 457

342 343 458

347 348 459

359 360 460

323 324 461

294 295

Method AX

Method AX, Step 1.

A literature procedure was adapted. (J-Q Yu and E. J. Corey, OrganicLetters, 2002, 4, 2727-2730).

To a 400 ml DCM solution of AX1 (n=1, R⁴=phenethyl) (52 grams) in a icebath was added 5 g of Pd/C (5% w/w), 50 g of potassium carbonate and 100ml of anhydrous t-BuOOH. The mixture was stirred in air for overnightbefore it was diluted with DCM and washed with water. The residue afterremoval of organic solvent and drying was chromatographed usingethylacetate/hexane to give 25 g of AX2 (n=1, R⁴=phenethyl).

Method AX, Step 2.

A solution of AX2 (4.5 g, n=1, R⁴=phenethyl) in MeOH (50 ml) was treatedwith 0.4 g of Sodium borohydride and the reaction was stirred for 30 minbefore the solvent was removed and residue chromatographed to give amixture of AX3 (n=1, R⁴=phenethyl) and AX4 (n=1, R⁴=phenethyl) which wasseparated using an AS chiralpak column eluted with 8% IPA in Hexane(0.05% DEA) to give 2.1 g of AX3 (n=1, R⁴=phenethyl) as the firstfraction and 2.2 g of AX4 (n=1, R⁴=phenethyl) as the second fraction.

Method AX, Step 3.

A 100 ml methanolic solution of AX4 (n=1, R⁴=phenethyl) (2.2 g) and1,1′-bis(di-1-propylphosphino)ferrocene (1,5-cyclooctadiene)rhodium (I)tetrafluoroborate (0.4 g, 0.57 mmol) was hydrogenated at 55 psiovernight. The reaction was concentrated, and the brown oil was purifiedby silica gel chromatography to yield AX6 (n=1, R⁴=phenethyl) (1.7 g).

The following compounds were generated using similar method.

Method AY

A solution of AY1 (n=1; 1.5 g, 3.4 mmol), 5% Rh/C (1.5 g), 5% Pd/C (0.5g) in ACOH (30 mL) was shaken in a Parr apparatus at 55 psi for 18hours. The vessel was flushed with N₂, and the reaction was filteredthrough a pad of celite. After concentration AY2 was obtained which wascarried on without purification. MS m/e: 312.0 (M+H).

AY3 was generated using similar method.

Method AZ

Method AZ, Step 1

To a solution of AZ1 (n=1, R¹=Me, R³=3=2-cyclohexylethyl) (0.441 g, 1.01mmol), generated from AY2 using Method C and Method H Step 3, in DCM wasadded Dess-Martin Periodinane (0.880 g, 2.07 mmol). The reaction wasstirred for 3 hours at room temperature. The reaction was quenched withH₂O and diluted with EtOAc. After removal of the organic phase, theaqueous layer was extracted with EtOAc (3×). The combined organics weredried (Na₂SO₄), filtered, and concentrated. The residue was purified bysilica gel chromatography (0-100% EtOAc/hexanes) to yield AZ2 (n=1,R¹=Me, R³=2-cyclohexylethyl) (0.408 g, 0.94 mmol, 93% yield). MS m/e:434.1 (M+H).

Method AZ Step 2:

To a solution of AZ2 (n=1, R¹=Me, R³=2-cyclohexylethyl) (0.011 g, 0.025mmol) and AZ5 (R¹⁵═H and R16=m-pyridylmethyl) (0.0067 mL, 0.066 mmol) inDCE (1.8 mL) and MeOH (0.2 mL) was added AcOH (4 drops) andMP-cyanoborohydride resin (0.095 g, 2.42 mmol/g). The reaction wasagitated for 40 hours at room temperature. The reaction was treated with7N NH₃/MeOH, and solution was filtered. After concentration, the residuewas purified by silica gel HPLC (0-4% [(5% 7N NH₃/MeOH)/MeOH]/(50%DCM/hexanes) to furnish fraction 1 and fraction 2 which, after removalof solvent, were treated with 20% TFA in DCM for 3 h at r.t. to give AZ4(n=1, R¹=Me, R³=2-cyclohexylethyl, R⁵═H and R¹⁶=m-pyridylmethyl) (0.005g, 0.009 mmol) and the AZ3 (n=1, R¹=Me, R³=2-cyclohexylethyl, R¹⁵═H andR¹⁶=m-pyridylmethyl) (0.012 g, 0.022 mmol) respectively.

The following compounds were generated using similar methods:

Obs. # Structure MW m/e 462

333 334 463

348 349 464

374 375 465

374 375 466

374 375 467

374 375 468

376 377 469

376 377 470

376 377 471

376 377 472

377 378 473

377 378 474

378 379 475

378 379 476

388 389 477

388 389 478

388 389 479

388 389 480

388 389 481

388 389 482

388 389 483

388 389 484

390 391 485

390 391 486

390 391 487

390 391 488

391 392 489

391 392 490

391 392 491

391 392 492

392 393 493

392 393 494

392 393 495

392 393 496

402 403 497

402 403 498

402 403 499

405 406 500

406 407 501

406 407 502

406 407 503

406 407 504

406 407 505

410 411 506

410 411 507

410 411 508

411 412 509

411 412 510

411 412 511

416 417 512

416 417 513

416 417 514

416 417 515

417 418 516

417 418 517

424 425 518

424 425 519

424 425 520

424 425 521

425 426 522

425 426 523

425 426 524

425 426 525

425 426 526

425 426 527

425 426 528

425 426 529

425 426 530

425 426 531

425 426 532

425 426 533

428 429 534

428 429 535

439 440 536

439 440 537

442 443 538

442 443 539

442 443 540

442 443 541

444 445 542

445 446 543

459 460 544

459 460

Method BA

Method BA, Step 1:

BA1, prepared according to a literature procedure (Terao, Y; Kotaki, H;N and Achiwa K. Chemical and Pharmaceutical Bulletin, 33 (7), 1985,2766) was converted to BA2 using a procedure described by Coldham, I;Crapnell, K. M; Fernandez, J-C; Moseley J. D. and Rabot, R. (Journal ofOrganic Chemistry, 67 (17), 2002, 6185-6187).

¹H NMR (CDCl₃) for BA2: 1.42 (s, 9H), 4.06 (d, 4H), 4.09 (s, 1H), 4.18(s, 2H), 5.62 (d, 1H).

Method BA, Step 2:

BA3 was generated from BA2 using a literature procedure described byWinkler J. D.; Axten J.; Hammach A. H.; Kwak, Y-S; Lengweiler, U.;Lucero, M. J.; Houk, K. N. (Tetrahedron, 54 1998, 7045-7056). Analyticaldata for compound BA3: MS m/e: 262.1, 264.1 (M+H). ¹H NMR (CDCl₃) 1.43(s, 9H), 3.98 (s, 2H), 4.11 (d, 4H), 5.78 (d, 1H).

Method BB

Method BB, Step 1;

Compound BB1 (n=1, R¹=Me, R³=cyclohexylethyl) was converted to BB2 (n=1,R¹=Me, R³=cyclohexylethyl) and BB3 (n=1, R¹=Me, R³=cyclohexylethyl)which were separated via a silica gel column eluted with EtOAc in Hexane(0-15%).

Method BB, Step 2;

Compound BB4 (n=1, R¹=Me, R³=cyclohexylethyl) was generated from BB2(n=1, R¹=Me, R³=cyclohexylethyl) using 20% TFA in DCM.

The following compounds were generated using similar method:

Method BC

Method BC, Step 1;

Compound BC2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) wasobtained from BC1 (n=1, R²=Me, R³=cyclohexylethyl) using method L step2.

Method BC, Step 2;

Compound BC3 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) wasobtained from BC2 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl)using method L step 3.

The following compounds were generated using a similar method:

Obs. # Structure MW m/e 552

374 375 553

388 389 554

388 389 555

388 389 556

388 389 557

390 391 557

390 391 559

402 403 560

402 403 561

402 403 562

402 403 563

404 405 564

404 405 565

404 405 566

404 405 567

410 411 568

410 411 569

411 412 570

411 412 571

411 412 572

411 412 573

411 412 574

411 412 575

416 417 576

416 417 577

416 417 578

416 417 579

424 425 580

424 425 581

424 425 582

424 425 583

425 426 584

425 426 585

425 426 586

425 426 587

425 426 588

425 426 589

425 426 590

430 431 591

430 431 592

438 439 593

438 439 594

439 440

Method BD

Method BD, Step 1;

Compound BD2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=Ph) was obtainedfrom BD1 (n=1, R²=Me, R³=cyclohexylethyl) using Method N, Step 1.

Method BD, Step 2;

Compound BD3 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=Ph) was obtainedfrom BD2 (n=1, R¹=Me, R³=cyclohexylethyl and R¹⁵=m-Pyridyl) using MethodN, Step 2.

The following compounds were generated using a similar method:

Obs. # Structure MW m/e 595

440 441 596

460 461

Method BE

Method similar to Method M was adapted for these transformations. Thefollowing compounds were generated similar methods.

Obs. # Structure MW m/e 597

405 406 598

439 440

Method BF

Method BF, Step 1:

Method similar to Method T, Step 1 was used for the synthesis of BF2(n=Me and R³=phenethyl, R¹⁵═H and R¹⁶=n-propyl).

Method BF, Step 2:

Method similar to method L Step 3 was adapted for this transformation.

The following compounds were generated using similar methods.

Obs. # Structure MW m/e 599

376 377 600

390 391 601

390 391 602

390 391 603

397 398 604

397 398 605

397 398 606

397 398 607

411 412

Method BG

Method BG:

To a solution of BG1 (n=1, R³=cyclohexylethyl) (0.136 g, 0.31 mmol) inCH₂Cl₂ was added 2,6-lutidine, AgOTf, and butyl iodide. The reaction wasstirred at room temperature for 96 hours. The reaction was filteredthrough a pad of Celite, and the solution was concentrated. The residuewas purified by silica chromatography (0-100% EtOAc/hexanes) to furnishBG2 (n=1, R³=cyclohexylethyl, R¹⁵=n-butyl) (0.124 g, 0.25 mmol, 80%yield). MS m/e: 426.1 (M-OBu).

The following compound was prepared using similar method:

Method BH

Method BH, Step 1.

Compound BH1 (n=1, R³=cyclohexylethyl and R¹⁵=n-butyl) (0.060 g, 0.12mmol) and 5% Pd(OH)₂/C (0.040 g) in EtOAc (1 mL)/MeOH (0.2 mL) wasstirred under an atmosphere of H₂ for 20 hours at room temperature. Thereaction was filtered through a pad of Celite, and the solution wasconcentrated. The crude product mixture BH2 (n=1, R³=cyclohexylethyl andR¹⁵=n-butyl) was carried on to the next step without purification.

Method BH, Step 2.

A solution of BH2 (n=1, R³=cyclohexylethyl and R¹⁵=n-butyl) wasconverted to a product mixture of BH4 and BH3 using a method similar toMethod C Step 1. The mixture was purified by silica gel chromatographyusing EtOAc/hexanes to yield BH4 (n=1, R²=Me, R³=cyclohexylethyl andR¹⁵=n-butyl) (0.032 g, 0.078 mmol, 56% yield) and BH3 (n=1, R²=Me,R³=cyclohexylethyl and R¹⁵=n-butyl) (0.008 g, 0.020 mmol, 14% yield).For BH4 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl), MS m/e:409.1M+H). For BH3 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl), MSm/e: 409.1 (M+H).

Method BH, Step 3.

Compound BH4 (n=1, R²=Me, R³=cyclohexylethyl and R¹⁵=n-butyl) (0.032 g,0.078 mmol) was converted to BH5 (n=1, R²=Me, R³=cyclohexylethyl andR¹⁵=n-butyl) (0.016 g, 0.043 mmol, 57% yield) using a method similar toMethod A, step 3. MS m/e: 392.1 (M+H).

The following compound was generated using a similar method:

Obs. # Structure MW m/e 608

391 392 609

391 392 610

391 392

Method BI

A solution of BI1 (0.020 g, 0.040 mmol) in DCM (1 mL) was degassed usingfreeze/pump/thaw (4×) method. At the end of the fourth cycle Crabtree'scatalyst was added and the system was evacuated. While thawing, thesystem was charged with hydrogen gas, and the reaction was stirred atroom temperature for 16 hours under an H₂ atmosphere. The reaction wasconcentrated, and the brown oil was purified by reverse phase HPLC tofurnish BI2(0.011 g, 0.022 mmol, 55% yield). MS m/e: 368.2 (M+H).

Method BJ

Method BJ, Step 1

A mixture of 2 ml dioxane solution of BJ1 (R¹=Me, R³=Me) (140 mg, 0.5mmol) generated using Method BK Steps 1 & 2, indole (1.2 eq), potassiumt-Butoxide (1.4 eq), Pd₂(dba)₃ (0.02 eq) and2-di-t-butylphospinobiphenyl (0.04 eq) in a sealed tube was irradiatedin a microwave oven at 120° C. for 10 min and the mixture was separatedvia a silica gel column to give BJ2 (R¹=Me, R³=Me) (0.73 mg).

Method BJ, Step 2

BJ2 (R¹=Me, R³=Me) was converted to BJ3 (R¹=Me, R³=Me) using Method BK,Steps 3 & 4. Obs. Mass for BJ3 (R¹=Me, R³=Me): 319.2.

Obs. # Structure MW m/e 614

318 319

Method BK

Method BK, Step 1:

Hydantoin BK2 (R³═N-benzyl-3-piperidyl, R⁴=n-Bu) was prepared accordingto Method D, Step 1 from the corresponding ketone BK1(R³═N-benzyl-3-piperidyl, R⁴=n-Bu). Analytical data for BK2(R³═N-benzyl-3-piperidyl, R⁴=n-Bu): (M+H)=330.1.

Method BK, Step 2:

To a suspension of hydantoin BK2 (R³═N-benzyl-3-piperidyl, R⁴=n-Bu) (138mg, 0.419 mmol) in DMF (1.5 ml) was added dimethylformamidedimethylacetal (0.11 ml, 0.84 mmol). The resulting mixture was heated ina 100° C. oil bath for 16 h and then cooled to RT and concentrated undervacuum. This crude residue was purified by column chromatography(MeOH/DCM) to give product BK3 (R³═N-benzyl-3-piperidyl, R⁴=n-Bu) (140mg, 0.408 mmol, 97%), (M+H)=344.1.

Method BK, Step 3:

To a solution of a portion of BK3 (R³═N-benzyl-3-piperidyl, R⁴=n-Bu) (70mg, 0.20 mmol) in toluene (1 ml) was added Lawesson's reagent (107 mg,0.26 mmol). The resulting mixture was placed in an oil bath at 60° C.for 16 h and then at 100° C. for 24 h. After cooling to RT, the reactionwas quenched by addition of several drops of 1 N HCl and then dilutedwith EtOAc and 1 N KOH. The phases were separated and the aqueous layerextracted with EtOAc (2×). The organic portions were combined, washedwith brine, dried over MgSO₄, filtered, and concentrated. This cruderesidue was purified by preparative TLC (1000 μm silica, 15% EtOAc/DCM)to give two separated diastereomers BK4 (R³═N-benzyl-3-piperidyl,R⁴=n-Bu) (24 mg, 0.067 mmol, 33%, MS: (M+H)=360.2) and BK5(R³═N-benzyl-m-piperidyl, R⁴=n-Bu) (22 mg, 0.062 mmol, 31%, MS: (M+H)360.2).

Method BK, Step 4:

Diastereomer BK5 (R³═N-benzyl-3-piperidyl, R⁴=n-Bu) was treated withNH₄OH (2 ml) and t-butyl hydrogen peroxide (70% aqueous, 2 ml) in MeOH(4 ml) for 24 h. After concentration, the crude sample was purified bypreparative TLC (1000 mm silica, 7.5% 7N NH₃/MeOH in DCM). The resultingsample was dissolved in DCM (1 ml), treated with 4N HCl in dioxane for 5min, and finally concentrated to give diastereomeric products BK7(R³═N-benzyl-3-piperidyl, R⁴=n-Bu) (12 mg, 0.029 mmol, 43%). ¹H NMR(CD₃OD) δ 7.60 (m, 2H), 7.49 (m, 3H), 4.39 (ABq, J_(AB)=12.8 Hz,Δν_(AB)=42.1 Hz, 2H), 3.69 (m, 1H), 3.39 (br d, J=13.6 Hz, 1H), 3.20 (s,3H), 2.96 (m, 2H), 2.45 (m, 1H), 1.99 (m, 1H), 1.92-1.78 (m, 3H), 1.68(br d, J=12.4 Hz, 1H), 1.50 (dq, J_(d)=3.6 Hz, J_(q)=12.8 Hz, 1H),1.36-1.22 (m, 4H), 1.03 (m, 1H), 0.90 (t, J=7.2 Hz, 3H). LCMS: t_(R)(doubly protonated)=0.52 min, (singly protonated)=2.79 min; (M+H) forboth peaks=343.2.

The following compounds were synthesized using similar methods:

Obs. # Structure MW m/e 615

218 219

Method BL

To a 2 ml Methanolic solution of BL1 (n=1, R³=cyclohexylethyl, R¹=Me)(10 mg) was added BL3 (HCl salt, R¹⁵═H, 2 eq) and NaOAc (2 eq) and themixture was heated to 60 C for 16 h. After removal of solvent, theresidue was treated with 20% TFA in DCM for 30 min before the solventwas evaporated and residue purified using a reverse phase HPLC to giveBL2 (n=1, R³=cyclohexylethyl, R¹=Me and R¹⁵═H).

The following compounds were synthesized using similar methods.

Obs. # Structure MW m/e 616

348 349 617

388 389

Method BM

Method BM, Step 1:

To a toulene solution (3 ml) of BM1 (n=1, R³=cyclohexylethyl, R²=Me)(0.050 mg) was added 1.5 eq of diphenylphosphorylazide and 1.5 eq of DBUand the solution was stirred at r.t. overnight. The reaction mixture wasdiluted with EtOAc and washed with 1% aq HOAc before the organic layerwas dried and solvent evaporated. The residue was chromatographed usingEtOAc/Hex to give a product that was treated with triphenylphosphine (2eq) in THF (1% water) overnight to give BM2 (n=1, R³=cyclohexylethyl,R²=Me) after reverse phase purification.

Method BM Step 2:

To a DCM solution of BM2 (n=1, R³=cyclohexylethyl, R²=Me) was added 1 eqof benzyloxycarbonyl-OSu and the reaction was stirred overnight beforethe solvent was evaporated and residue chromatographed to give BM3 (n=1,R³=cyclohexylethyl, R²=Me).

Compound BM4 (n=1, R³=cyclohexylethyl, R²=Me) and BM5 (n=1,R³=cyclohexylethyl, R²=Me) were generated from BM2 (n=1,R³=cyclohexylethyl, R²=Me) and BM3 (n=1, R³=cyclohexylethyl, R²=Me)through Boc-deprotection.

The following compounds were synthesized using similar method:

Obs. # Structure MW m/e 618

332 333 619

468 469

Method BN

A mixture of Pd(OAc)₂ (9 mg), triethylamine (17 microliter),triethylsilane (11 microliter) and BN1 (20 mg) in DCM was hydrogenatedat 1 atm at rt for 1.5 h before the reaction was filtered through aCelite pad to give BN2 after removal of solvent.

Method BO

The following compounds were generated through boc-deprotection of thecorresponding starting material using 50% TFA in DCM, rt 30 min.

Obs. # Structure MW m/e 620

266 267 621

266 267 622

274 275 623

274 275 624

288 289 625

320 321 626

320 321

Method BP

Method BP, Step 1

To a solution of BP1 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.012 g,0.028 mmol) in CH₂Cl₂ (0.5 mL) was added 2,6-lutidine (0.010 mL, 0.086mmol), AgOTf (0.024 g, 0.093 mmol), and benzyl bromide (0.010 mL, 0.084mmol). The reaction was stirred at room temperature for 16 hours. Thesolid was filtered, and after concentration the residue was purified byreverse phase HPLC to yield BP2 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl)(0.010 g, 0.019 mmol). MS m/e: 526.1 (M+H).

Method BP, Step 2

BP3 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) was prepared from BP2 (n=1,R¹=Me, R²═H, R³=cyclohexylethyl) using 30% TFA/DCM. MS m/e: 426.1 (M+H).

Obs. # Structure MW m/e 627

425 426

Method BQ

Method BQ Step 1:

BQ1 was prepared according to Method AZ.

To a solution of BQ1 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.004 g,0.007 mmol) in CH₂Cl₂ (0.3 mL) was added DIEA (0.007 mL, 0.040 mmol),acetic acid (0.001 mL, 0.017 mmol), HOBt (0.003 g, 0.019 mmol), and EDCl(0.003 g, 0.016 mmol). The reaction was stirred at room temperature for16 hours. The reaction was concentrated and purified by reverse phaseHPLC to provide BQ2 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.003 g,0.005 mmol). MS m/e: 627.1 (M+H).

Method BQ Step 2:

BQ2 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.003 g, 0.005 mmol) wastreated with 20% TFA/CH₂Cl₂ (1 mL) in the presence of PS-thiophenolresin (0.030 g, 1.42 mmol/g) for 3 hours. The solution was filtered andconcentrated to produce BQ3 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl)(0.002 g, 0.005 mmol). MS m/e: 377.2 (M+H).

Obs. # Structure MW m/e 628

376 377

Method BR

Method BR, Step 1:

To a solution of BR1 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.004 g,0.007 mmol) in pyridine (0.2 ml) was added DMAP (a few crystals) andmethylsulfonyl chloride (3 drops). The reaction was stirred at roomtemperature for 6 days. The reaction was quenched with water and dilutedwith CH₂Cl₂. The organic layer was removed, and the aqueous phase wasextracted with CH₂Cl₂ (3×). After concentration, the brown residue waspurified by reverse phase HPLC to yield BR2 (n=1, R¹=Me, R²═H,R³=cyclohexylethyl) (0.003 g, 0.004 mmol). MS m/e: 663.2 (M+H).

Method BR, Step 2:

BR3 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) was prepared from BR2 (n=1,R¹=Me, R²═H, R³=cyclohexylethyl) following a procedure similar to MethodBQ Step 2. MS m/e: 413.1 (M+H).

Obs. # Structure MW m/e 629

412 413

Method BS

Method BS Step 1:

To a solution of BS1 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.003 g,0.006 mmol) in CH₂Cl₂ (0.3 mL) was added phenyl isocyanate (2 drops).The reaction was stirred at room temperature for 16 hours. The reactionwas concentrated and purified by reverse phase HPLC to provide BS2 (n=1,R¹=Me, R²═H, R³=cyclohexylethyl) (0.002 g, 0.002 mmol). MS m/e: 823.5(M+H).

Method BS Step 2:

Compound BS2 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) was subjected to thesame conditions in Method BQ Step 2. The crude mixture prepared abovewas treated with LiOH (0.006 g, 0.25 mmol) in MeOH (0.3 mL) for 2 hours.The reaction was concentrated, and the residue was purified by reversephase HPLC to furnish BS3 (n=1, R¹=Me, R²═H, R³=cyclohexylethyl) (0.0012g, 0.002 mmol). MS m/e: 454.1 (M+H).

Obs. # Structure MW m/e 630

453 454

Method BT:

Method BT

To a round bottom flask were added compound BT1 (R¹=Me, R³=Me) (100 mg,0.29 mmol), anhydrous toluene (2 ml), 3-aminopyridine (55 mg, 0.58 mmol)and 2-(di-tert-butyl phosphino) biphenyl (17 mg, 0.058). The solutionwas then degassed by N₂ for 2 minutes before NaO-t-Bu (61 mg, 0.638mmol) and Pd₂(dba)₃ (27 mg, 0.029 mmol) were added. The reaction wasstirred at 80° C. for 22 hours. After cooling down to room temperature,the reaction was poured to cold water and extracted by CH₂Cl₂. Thecombined organic layer was then dried over Na₂SO₄. After the filtration,the concentrated residue was separated by TLC (CH₃OH:CH₂Cl₂=1:10) andreverse phase HPLC (10%-100% acetonitrile in water w/0.1% formic acid)to produce the desired compound BT2 (R¹=Me, R³=Me and R²¹=m-pyridyl) asa formate salt (23.6 mg, white solid, 20%). ¹HNMR (CDCl₃) δ 7.50-6.90(m, 13H), 3.14 (s, 3H) MS m/e 358 (M+H).

Obs. # Structure MW m/e 631

347 348 632

356 357 633

357 358 634

357 358 635

357 358 636

358 359

Method BU

Method BU, Step 1,

To a round bottomed flask containing BU1 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (99 mg, 0.307 mmol) of the trifluoroacetic acid saltof pyrollidone derivative in 5 ml of DCM was added (86 μL, 0.614 mmol)of triethylamine followed by addition of (76 mg, 0.307 mmol)N-(benzyloxycarbonyloxy)succinimide. Stir at room temperature for 18 h.Dilute the mixture with DCM and extract with sat'd NaHCO₃ soln, thenwater. Collect the organic portion and dry over Na₂SO₄, filter andconcentrate in vacuo. Purify by silica gel chromatography (eluting with0 to 60% EtOAc/hexanes) to yield BU2 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (130 mg, 0.284 mmol, 93% yield). MS m/e: 458.1(M+H).

Method BU, Step 2

To a solution of BU2 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (130 mg) in 1ml of MeOH in a reaction vial was added 0.5 ml of a solution of 70%tBuOOH in water and 0.5 ml of NH₄OH. Seal the vial and shake at roomtemperature for 72 h. The mixture was concentrated in vacuo. The mixturewas diluted with 1 ml of MeOH and a mixture 30 mg of NaHCO₃ and Boc₂O(87 mg, 0.398 mmol) were added. The solution mixture was stirred at roomtemperature for 18 h before it was concentrated and the residue purifiedby silica gel chromatography using EtOAc/hexanes to yield the BU3 (m=1,n=1, R¹=Me, R³=Cyclohexylethyl) (90 mg, 0.167 mmol, 58% yield). MS m/e:541.1, 441.1 (M+H).

Method BU, Step 3,

A solution of BU3 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (90 mg, 0.167mmol) in 5 ml of MeOH was hydrogenated using 100 mg of Pd(OH)₂—C (20%w/w) at 1 atm for 1 h. The reaction mixture was filtered through a padof diatomaceous earth and the pad was washed with MeOH. Concentration ofthe collected organic portions in vacuo yielded BU4 (m=1, n=1, R¹=Me,R³=Cyclohexylethyl) (47 mg 0.116 mmol, 70% yield). MS m/e: 407.1 (M+H).

Method BU, Step 4,

To a vial containing 10 mg of powdered 4 4′ molecular sieves was added3-methoxyphenyl boronic acid (60 mg, 0.395 mmol) then 3 ml of anhydrousMeOH. To this mixture was added pyridine (100 ml, 0.650 mmol), Cu(OAc)₂(7 mg, 0.038 mmol), and BU4 (m=1, n=1, R¹=Me, R³=Cyclohexylethyl) (7.83mg, 0.019 mmol) and the mixture was stirred at room temperature for 96 hbefore it was quenched with 0.25 ml of 7N ammonia in methanol solution.The reaction mixture was extracted with water and DCM and the organiclayers were dried and concentrate in vacuo. The residue was purified viaa reverse-phase HPLC to give a product which was treated with 5 ml of40% of TFA in DCM for 5 h. After removal of the volatiles, the residuewas purified using a reverse phase HPLC system to furnish BU5 (m=1, n=1,R¹=Me, R³=Cyclohexylethyl and R²¹=m-MeOPh) as the formic acid salt (0.7mg, 0.0015 mmol, 30.1% yield). MS m/e: 413.1 (M+H).

Obs. # Structure MW m/e 637

358 359 638

412 413

Method BV

Method BV Step 1:

The method was adapted from a literature procedure (Page et al.,Tetrahedron 1992, 35, 7265-7274)

A hexane solution of nBuLi (4.4 mL, 11 mmol) was added to a −78 Csolution of BV2 (R⁴=phenyl) (2.0 g, 10 mmol) in THF (47 mL). After 60minutes at −78 C, a solution of BV1 (R³=3-bromo-4-fluorophenyl) (2.24 g,11 mmol) was added and the reaction slowly warmed to RT over 18 h. Thereaction mixture was quenched with saturated ammonium chloride solutionand extracted with CH₂Cl₂ (2×), dried over MgSO4 and concentrated undervacuum. The resulting oil was subjected to silica gel chromatographyusing 4-10% EtOAc/Hexanes to give a white solid BV3(R³=3-bromo-4-fluorophenyl and R⁴=phenyl) (1.69 g, 4.23 mmol, 42%). ¹HNMR (CDCl₃) δ 7.61 (m, 2 H), 7.27 (m, 3 H), 6.94 (m, 1 H), 6.92 (m, 1H), 6.68 (m, 1 H), 3.15 (bs, 1H), 2.57-2.73 (m, 4 H), 1.89 (m, 2 H).

Method BV Step 2:

A solution of BV3 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl) (1.69 g,4.23 mmol) in acetone (40 mL) was slowly added via addition funnel to a0° C. solution of N-bromosuccinimide (NBS, 11.3 g, 63.3 mmol) in acetone(200 mL) and water (7.5 mL). The mixture was slowly warmed to RT, andquenched after 60 minutes with 10% aqueous Na₂SO₃. After diluting withCH₂Cl₂, the layers were separated, and the organic layer washed withwater (2×), brine (1×) and dried over MgSO₄. Concentration under vacuumafforded an oil which was subjected to silica gel chromatography using5% EtOAc/Hexanes to give a solid BV4 (R³=3-bromo-4-fluorophenyl andR⁴=phenyl) (690 mg, 2.24 mmol, 53%). ¹H NMR (CDCl₃) δ 8.19 (m, 1 H),7.93 (m, 3 H), 7.66 (m, 1 H), 7.50 (m, 2 H), 7.20 (m, 1 H).

Method BV Step 3:

BV5 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl and R¹=Me and R²═H) wasprepared from BV4 (R³=3-bromo-4-fluorophenyl and R⁴=phenyl) using MethodAS, Step 4.

Obs. # Structure MW m/e 639

361 362 640

361 NA

Method BW

To an oven-dried vial was added Pd₂(dba)₃ (15.4 mg, 0.0168 mmol) and2-(Di-t-butylphosphino)biphenyl (10.0 mg, 0.0336 mmol) followed byaddition of a solution of BW1 (R⁴=Me; R¹=Me and n=1) (56.8 mg, 0.168mmol) in 2 mL of anhydrous THF. 2-Bromopyridine (17.0 mL, 0.178 mmol)was added followed by addition of 0.80 mL of 1.0 N LHMDS solution inTHF. The reaction mixtures was stirred at 35° C. for 90 min followed byaddition of MeOH and filtration through a silica gel pad. Purificationby silica gel chromatography (0 to 100% EtOAc in hexanes) yielded theproduct which was treated with 5 mL of a 30% TFA in DCM solution to giveBW2 after concentration and purification via a reverse phase column(R⁴=Me; R¹=Me; R²²=2-pyridyl and n=1) (69.3 mg, 99%). ES_LCMS (m/e):416.2

Method BX

Method BX, Step 1

To a solution of BX1 (R⁴=Me and n=1) (0.78 g, 3.63 mmol) in 10 mL ofanhydrous DMF, was added N-Boc-N′-methyl thiourea (0.70 g, 3.70 mmol),EDCl.HCl (0.90 g, 4.71 mmol), and diisopropylethylamine (2.5 mL). Themixture was stirred at RT for 16 h before it was quenched with water andextracted with EtOAc (3×50 mL). The organic solution was dried,concentrated and the residue chromatographed via a silica gel column toyield BX2 (R¹═R4=Me and n=1) (1.23 g, 100%). ES_LCMS (m/e): 340.1

Method BX, Step 2

To a solution of BX2 (R¹═R⁴=Me and n=1) (1.23 g, 3.63 mmol) in 40 mL ofanhydrous THF was added triphenylphosphine (1.43 g, 5.44 mmol) and themixture was cooled to 0° C. followed by slow addition ofdiisopropylcarbodiimide (1.07 mL, 5.44 mmol). After the mixture wasstirred for 15 min at 0° C., nicotinoyl azide (Synthesis, 2004 (17),2886) (0.66 g, 4.71 mmol) was added in one portion and the reaction wasallowed to warm to RT and stir for 3 h. The reaction was diluted withEtOAc (200 mL) and washed with water (3×100 mL). The residue from theorganic layer was purified through a silica gel column to yield theproduct azide which was hydrogenation using 20% Pd(OH)₂/C (0.64 mg) inMeOH to give BX3 (R¹═R⁴=Me and n=1). ES_LCMS (m/e): 339.1.

Method BY

The following compounds were synthesized using methods similar toMethods AO or AP.

Method BZ

The following aminoacids were generated using methods similar to MethodD

Method CA

Compound CA2 (R³═R⁴=Ph; Z=m-phenylene, R¹⁵═H and R¹⁶=cyclopentyl) wasobtained from CA1 (R³═R⁴=Ph; Z=m-phenylene, R¹⁵═H and R¹⁶=cyclopentyl)using a method similar to Method G.

Method CB

The following compounds were synthesized using methods similar to MethodE and/or AX.

Method CC

Method CC, Step 1.

To a methanol solution (20 mL) of CC1 (5 g) cooled to 0° C. was addedsodium borohydride (1 eq) and the reaction was stirred for 30 min beforethe reaction mixture was evaporated to dryness then extracted withDCM/water. The DCM fractions were pooled, dried (MgSO₄), filtered andconcentrated to dryness. The crude product was dissolved in 20 mL. ofanhydrous DCM. To this solution was added t-butyldimethylchlorosilane (2eq.) and imidazole (2 eq.). The reaction was stirred overnight at RTbefore it was quenched DCM and saturated NaHCO₃. The organic phase wasdried (MgSO₄), filtered and evaporated to dryness to give crude productCC2.

Method CC, Step 2.

A literature procedure was adapted (Aust. J. Chem. 1990, 43(7), 1195).Compound CC2 (50 g) in 80 mL. THF was added to mercuric oxide (1.5 eq.)and borontrifluoride etherate (1.6 eq.) in 540 mL. of THF/H₂O (5:1) andthe mixture was stirred under nitrogen for 2 h before the reaction wasquenched with saturated NaHCO₃ (aq.) and ether. The ether phase wasdried over anhyd. Na₂SO₄, filtered through a silica pad and concentratedto give crude CC3.

Method CC, Step 3.

To CC3 (10.4 grams) in 200 mL MeOH was added 1.1 eq. of sodiumborohydride and the mixture was stirred for 30 min before the reactionmixture was concentrated and the residue partitioned in DCM/H₂O. Theorganic phase was dried over Na₂SO₄, filtered and concentrated. Theresidue was chromatographed to give product CC4.

Method CC, Step 4.

Compound CC4 (2.5) in 5 mL. anhydrous DCM was addedBis(1,2-diphenylphosphino)ethane (DPPE; 1.2 eq.) followed by carbontetrabromide (1.1 eq.) at 0° C. and the reaction was stirred for 30 min.The reaction was quenched with hexane and poured over a silica pad. Theorganic solution was evaporated to give product CC5 as an oil. ¹H-NMR(CDCl₃) δ 5.72, br s, 1H, 4.18, t, 1H, 3.83, q, 2H, 2.00-2.10, m, 2H,1.76-1.81, m, 2H, 1.43-1.56, m, 2H, 0.84, s, 9H, 0.03, s, 6H.

Method CC, Step 5

Compound CC6 was generated from CC5 using a similar procedure in MethodE. Crude compound CC6 was purified by flash chromatography (gradient0-10% EtOAc in hexane). Two isomers were isolated during purificationisomer A which eluted first followed by isomer B.

ISOMER A: ¹H-NMR (CDCl₃) δ 7.26-7.37, m, 5H, 5.57, s, 1H, 5.38, s, 1H,5.02, q, 2H, 4.08, br s, 1H, 3.67, s, 3H, 3.08, d, 1H, 2.58, d, 1H,1.80-1.92, m, 1H, 1.60-1.75, m, 3H, 1.32-1.44, m, 3H, 0.83, s, 9H,0.35-0.45, m, 4H, 0.01, s, 6H.

ISOMER B: ¹H-NMR (CDCl₃) δ 7.286-7.36, m, 5H, 5.56, s, 1H, 5.39, s, 1H,5.06, q, 2H, 4.15, br s, 1H, 3.71, s, 3H, 3.06, d, 1H, 2.70, d, 1H,1.60-1.90, m, 4H, 1.33-1.48, m, 3H, 0.87, s, 9H, 0.37-0.51, m, 4H, 0.03,s, 6H. Yield 26% isomer A and 22% isomer B.

Method CC, Step 6

Compound CC7 was obtained from CC6 (isomer B) through treatment with 1 NTBAF in THF for 30 min followed by extraction with ether/water. Theorganic phase was separated and washed four times with water. Theaqueous phase was pooled and washed once with Et₂O (pH ˜6 to 7). Theorganic phase was dried over Na₂SO₄, filtered and evaporated to giveproduct CC7 in 94% yield. ¹H-NMR (CDCl₃) δ 7.28-7.39, m, 5H, 5.58, brs,1H, 5.49, brs, 1H, 5.10, d, 1H, 5.02, d, 1H, 4.09, brs, 1H, 3.72, s, 3H,3.14, d, 1H, 2.70, s, 1H, 1.79-1.87, m, 2H, 1.67-1.79, m, 1H, 1.53-1.67,m, 2H, 1.44-1.53, m, 2H.; 1.31-1.39, m, 1H, 0.35-0.54, m, 4H

Method CD

Step 1: tert-Butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate

To a solution of tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (CD1; R⁴=Me) (1.5 g, 4.6mmol) in EtOAc (150 mL) at reflux was added IBX (3.82 g, 13.6 mmol, 3eq). Reflux was continued for another 2 h and then the mixture wascooled to RT. The white precipitate was filtered and the filtrate wasconcentrated. The residue was purified by chromatography on silica gelby eluting with EtOAc/hexanes to give 1.0 g (66%) of tert-butyl2-(3-bromophenyl)-1-oxopropan-2-yl carbamate (CD2; R⁴=Me) as a colorlessoil. ¹H NMR (CDCl₃) δ 9.42 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H),7.55-7.40 (m, 2H), 5.85 (bs, 1H), 1.96 (s, 3H), 1.56 (s, 9H).

Step 2: tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate(CD2; R⁴=Me) (1.0 g, 3 mmol) in dichloroethane (50 mL) was addedmethylamine (0.48 g, 6.1 mmol, 2 eq) in water (40%) and 1 mL of AcOH.The solution was allowed to stir at RT for 1 h followed by the additionof sodium triacetoxyborohydride (1.8 g, 8.5 mmol, 2.8 eq). The resultingmixture was stirred at RT for 16 h and quenched with MeOH. Afterstirring for 30 min the mixture was concentrated in vacuo. The residuewas purified by chromatography on silica gel by eluting with EtOAc/MeOHto give 0.62 g (60%) of tert-butyl2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3; R¹=Me,R⁴=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.47 (bs, 1H), 7.37 (m, 1H),7.27 (m, 1H), 7.23 (m, 1H), 5.97 (bs, 1H), 3.18-2.82 (m, 2H), 2.45 (s,3H), 1.74 (s, 3H), 1.40 (s, 9H). MS (ESI) m/e 342.9 (M+H)⁺.

Step 3: 4-(3-Bromophenyl)-1,4-dimethylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methylamino)propan-2-ylcarbamate (CD3;R¹=Me, R⁴=Me) (0.62 g, 1.8 mmol) was dissolved in 25% TFA in DCM (25 mL)and the mixture was left stirring at RT for 1 h. The mixture wasconcentrated in vacuo and the residue was redissolved in CHCl₃ (20 mL).The solution was washed with 15% NaOH (10 mL) and the aqueous layer wasextracted with CHCl₃ (3×10 mL). The combined organic layer was driedover MgSO₄ and concentrated in vacuo to give 0.33 g (76%) of crude2-(3-bromophenyl)-N¹-methylpropan-1,2-diamine as a colorless oil. ¹H NMR(CDCl₃) δ 7.65 (t, J=1.7 Hz, 1H), 7.41-7.34 (m, 2H), 7.21 (t, J=7.8 Hz,1H), 2.86 (dd, J=11.7, 0.6 Hz, 1H), 2.64 (dd, J=11.7, 0.6 Hz, 1H), 2.38(s, 3H), 1.54 (bs, 3H), 1.43 (s, 9H). MS (ESI) m/e 242.9 (M+H)⁺. Thecompound was used in the next step without further purification.

To a solution of 2-(3-bromophenyl)-N¹-methylpropan-1,2-diamine (0.12 g,0.50 mmol) in EtOH (10 mL) was added BrCN (0.073 g, 0.70 mmol, 1.4 eq).The mixture was stirred at RT for 16 h and then concentrated in vacuo.The residue was redissolved in CHCl₃ (20 mL) and the solution was washedwith 15% NaOH (10 mL). The aqueous layer was extracted with CHCl₃ (3×10mL) and the combined organic layer was dried (MgSO₄), and concentratedto give 0.14 g (100%) of4-(3-bromophenyl)-1,4-dimethylimidazolidin-2-imine (CD4; R¹=Me, R⁴=Me)as a colorless oil. ¹H NMR (CDCl₃) δ 7.42 (t, J=1.7 Hz, 1H), 7.35 (dd,J=8.1, 1.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 3.62 (d, J=9.3 Hz, 1H), 3.53(d, J=9.0 Hz, 1H), 3.08 (s, 3H), 1.56 (bs, 3H). MS (ESI) m/e 268.1,270.1 (M+H)⁺.

Step 4:4-(3-(3,4-Difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (0.027 g, 0.1mmol, 1 eq), 3,4-difluorophenyl boronic acid (0.020 g, 0.13 mmol, 1.3eq), FibreCat (20 mg), anhydrous ethanol (2 mL), and a 1N K₂CO₃ aqueoussolution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in a microwave reactor(Emrys Optimizer) at 110° C. for 15 min. The mixture was transferred toa prepacked column of Si-carbonate (2 g, 0.79 mmol/g), which had beenconditioned with MeOH/DCM (1:1). The column was eluted with 1:1 MeOH/DCM(3×3 mL) and the eluants were collected and concentrated to give 0.019 g(63%) of4-(3-(3,4-difluorophenyl)phenyl)-1,4-dimethylimidazolidin-2-imine (CD5;R¹=Me, R⁴=Me, R²¹=3,4-difluorophenyl) as a white solid. ¹H NMR (CDCl₃) δ7.60 (s, 1H), 7.50-7.20 (m, 6H), 3.48 (m, 2H), 2.79 (s, 3H), 1.66 (s,3H). MS (ESI) m/e 302.2 (M+H)⁺, HPLC (A) R_(t)=5.48 min.

Alternative for Method CD for Compound: R¹═OR¹⁵

Alternative Method CD, Step 2: tert-Butyl2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate

To a solution of tert-butyl 2-(3-bromophenyl)-1-oxopropan-2-ylcarbamate(CD2; R⁴=Me) (2.7 g, 8.2 mmol) in dichloroethane (40 mL) was addedmethoxylamine hydrochloride (0.89 g, 10.7 mmol, 1.3 eq) and 1 mL ofAcOH. The solution was allowed to stir at RT for 16 h. The reactionmixture was concentrated to give the oxime intermediate. The oxime wasdissolved in EtOH (20 mL) and borane-pyridine complex (0.74 g, 7.9 mmol)was added dropwise. After stirring at r.t for 20 min, the reactionmixture was concentrated in vacuo. The residue was redissolved in DCM(50 mL) and washed with water (3×20 mL). The organic layer was dried(Na₂SO₄) and concentrated to give 1.6 g (54%) of tert-butyl2-(3-bromophenyl)-1-(methoxyamino)propan-2-ylcarbamate (CD3; R¹═OMe,R⁴=Me). ¹H NMR (CDCl₃) δ 7.60-7.10 (m, 4H), 5.82 (s, 1H), 3.90 (s, 3H),3.70 (m, 2H), 1.80 (s, 3H), 1.40 (s, 9H). The crude compound was used inthe next step without further purification.

Alternative Method CD, Step 3:4-(3-Bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine

tert-Butyl 2-(3-bromophenyl)-1-(methoxyamino)propan-2-yl carbamate (CD3;R¹=OMe, R⁴=Me) (1.6 g, 4.4 mmol) was dissolved in 25% TFA in DCM (25 mL)and the mixture was left stirring at RT for 1 h. The mixture wasconcentrated in vacuo. The residue was redissolved in CHCl₃ (20 mL) andwashed with 15% NaOH (10 mL). The aqueous layer was extracted with CHCl₃(3×10 mL). The combined organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was dissolved in EtOH (10 mL) andBrCN (0.096 g, 0.91 mmol) was added. After stirring at RT for 16 h, themixture was concentrated in vacuo. The residue was redissolved in CHCl₃(20 mL) and washed with 15% NaOH (10 mL). The aqueous layer wasextracted with CHCl₃ (3×10 mL). The combined organic layer was driedover MgSO₄ and concentrated to give 0.2 g (16%) of4-(3-bromophenyl)-1-methoxy-4-methylimidazolidin-2-imine (CD4; R¹=OMe,R⁴=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.65-7.35 (m, 4H), 4.02 (s,3H), 3.98 (d, 1H), 3.91 (d, 1H), 1.94 (s, 3H).

Alternative Method CD, Step 4:4-(3-(3-Chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine

A mixture of 4-(3-bromophenyl)-4-methyloxazolidin-2-imine (CD4; R¹═OMe,R⁴=Me) (0.027 g, 0.1 mmol, 1 eq), 3-chloro phenylboronic acid (0.023 g,0.13 mmol, 1.3 eq), FibreCat (0.020 g), anhydrous ethanol (2 mL), and 1NK₂CO₃ aqueous solution (0.12 mL, 0.12 mmol, 1.2 eq) was heated in amicrowave reactor (Emrys Optimizer) at 110° C. for 15 min. The mixturewas transferred to a prepacked column of Si-carbonate (2 g, 0.79mmol/g), which had been conditioned with MeOH/DCM (1:1). The column waseluted with 1:1 MeOH/DCM (3×3 mL) and the eluants were collected andconcentrated to give 0.008 g (25%) of4-(3-(3-chlorophenyl)phenyl)-1-methoxy-4-methylimidazolidin-2-imine(CD5; R¹═OMe, R⁴=Me, R²¹=3-ClC₆H₄) as a white solid. ¹H NMR (CDCl₃) δ7.75-7.60 (m, 5H), 7.58-7.42 (m, 3H), 4.00 (m, 2H), 3.97 (s, 3H), 1.97(s, 3H). MS (ESI) m/e 316.0, 318.0 (M+H)⁺, HPLC (A) R_(t)=5.64 min.

Method CE

Method CE, Step 1

The synthesis of CE2 (R¹═R⁴=Me, R²¹=Br and R⁴=Me) was adapted from theprocedure of Spanu, P. et. al., Tet. Lett., 2003, 44, 671-675. Thus, toa solution of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CE1; R¹═R⁶=Me, R²¹=Br) (0.24 g, 0.6 mmol, 1 eq) in THF (4 mL), LDA (2Min heptane/THF, 0.6 mL, 0.12 mmol, 2 eq) was added dropwise via asyringe at −78° C. After stirring at −78° C. for 30 min, a solution ofiodomethane (0.080 mL, 0.12 mmol, 2 eq) in THF (4 mL) was added dropwiseto form an orange-colored enolate solution. The mixture was stirred at−78° C. for 3 h. Water was added to quench the reaction and thesuspension was warmed to RT. The mixture was then partitioned betweenH₂O and Et₂O. The organic layer was separated and the aqueous layer wasextracted with Et₂O (3×25 mL).

The combined organic layers were washed with brine, dried (MgSO₄) andconcentrated to give 0.38 g of a brown oil. Chromatography on silica gelusing 50% EtOAc/hexanes as eluent gave 0.14 g (54%) of tert-butyl(4S,5R)-4-(3-bromophenyl)-1,4,5-trimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CE2; R¹═R⁴=Me, R²¹=Br and R⁶=Me) as a white solid. ¹HNMR (CDCl₃, 300MHz): δ 10.16 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 3.21 (s, 1H), 3.01(m, 3H), 3.02 (m, 1H), 1.51 (s, 12H), 1.17 (d, J=7.1 Hz, 3H). MS (ESI):MH⁺=441.7 HPLC (A) R_(t)=7.20 min.

Method CE, Step 2

A mixture of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CE2; R¹═R⁴=Me, R⁶=Me, R²¹═Br) (0.25 g, 0.6 mmol),5-cyanothien-1-ylboronic acid (0.2 g, 1.3 mmol, 2 eq), Fibrecat (4.26%Pd, 0.7 g), and 1N aq. K₂CO₃ (0.5 mL) was heated at 110° C. in a 20 mLSmith process vial using the Emrys microwave synthesizer. After cooling,the reaction mixture was transferred to a pre-packed column ofSi-Carbonate column and eluted with MeOH/CH₂Cl₂ (1:1). The eluent wasconcentrated to give 0.32 g of a yellow oil, which was purified bysilica gel chromatography (20-50% EtOAc/hexanes to give 0.13 g (0.3mmol, 48% yield, syn:anti ratio: 5:1) of (S)-tert-butyl4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxotetrahydro-pyrimidin-2(1H)-ylidenecarbamateas a white solid. ¹HNMR (CDCl₃, 300 MHz): δ 10.15 (s, 1H), 7.58-7.53 (m,3H), 7.53-7.38 (m, 2H), 7.23 (m, 1H), 3.32 (s, 3H), 3.16 (m, 1H), 1.57(s, 9H), 1.23 (d, J=6.9 Hz, 3H). MS (ESI): MH⁺=438.7; M+−56=383.1. HPLCR_(t)=7.28 min (syn isomer).

(S)-tert-Butyl4-(3-(5-cyanothien-1-yl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH₂Cl₂ at RT for 30min. The volatiles were removed in vacuo and the residue wasre-dissolved in acetonitrile (5 mL) and evaporated again to afford 17 mgof crude iminopyrimidinone as a yellow solid. The crude product waspurified by reverse phase HPLC (B) to provide 10 mg (60%) of(S)-6-(3-(5-cyanothien-1-yl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one(CE3; R¹═R⁴=Me, R⁶=Me, R²¹=5-cyanothien-1-yl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): δ 11.1 (brs, 1H), 10.0 (s, 1H), 7.58-7.53 (m, 3H),7.44 (m, 1H), 7.40-7.26 (m, 2H), 3.30 (m, 1H), 3.16 (s, 3H), 1.60 (s,3H), 1.27 (d, J=7.2 Hz, 3H). MS (ESI): MH⁺=438.7; M+−56=339.1. HPLCR_(t)=7.24 min (syn isomer).

Method CF

Method CF, Step 1.

To a solution of t-butylcarbamate (0.5 g, 4.3 mmol, 1 eq) in anhydrousTHF (5.0 mL) at RT was added NaH (0.17 g, 4.3 mmol, 1 eq). The mixturewas stirred at RT for 15 min. Then a solution of methyl isocyanate (0.3g, 4.2 mmol, 1 eq.) in anhydrous THF (5.0 mL) was added dropwise. Thereaction mixture was allowed to stir at 25° C. for 15 min. The mixturewas then poured into 30 mL of ice-water under vigorous stirring. Thereaction solution was extracted with Et₂O (2×25 mL). The organic layerswere combined and washed with brine (30 mL), dried (Na₂SO₄), andconcentrated in vacuo to give 0.42 g (50% yield) of tert-butylmethylcarbamothioylcarbamate CF1 (R¹=Me) as a white solid. ¹HNMR (CDCl₃,300 MHz): δ 8.3 (br s, 1H), 3.19 (d, 3H, J=4.8 Hz), 1.8 (br s, 1H), 1.5(s, 9H).

Method CF, Step 2.

To a solution of an HCl salt of AB2 (R⁶=3-bromophenyl and R⁷=Me) (0.2 g,0.7 mmol) and CF1 (R¹=Me) in DMF (2 mL) at RT was added DIEA (0.5 mL,2.8 mmol, 4 eq) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl(EDCl, 0.2 g, 1.0 mmol, 1.4 eq). After stirring at RT for 16 h, themixture was diluted with EtOAc (10 mL), washed with brine, dried(MgSO₄), and filtered. The filtrate was evaporated under reducedpressure to afford 0.34 g of crude product as a yellow oil which waspurified using silica gel chromatography by eluting with 20%EtOAc/hexanes to give 0.17 g (0.4 mmol, 60%) of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF2; R¹═R⁶=Me) as a white solid. ¹HNMR (CDCl₃, 300 MHz): δ 10.63 (s,1H), 7.42 (m, 2H), 7.24 (m, 2H), 3.21 (s, 3H), 3.2 (d, 1H, J=16.3 Hz),2.87 (d, 1H, J=16.1 Hz), 1.65 (s, 3H), 1.55 (s, 9H). MS (ESI):MH⁺=395.7, 398.7. HPLC R_(t)=7.11 min.

Method CF, Step 3.

A mixture of (S)-tert-butyl4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF2; R¹═R⁶=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid(R²¹=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26%of Pd, 0.7 g) and 1N aq. K₂CO₃ (0.5 mL) in dimethoxyethane (DME, 10 mL)or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stira bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min.After cooling, the reaction mixture was transferred to a pre-packedSi-Carbonate column and eluted with MeOH/CH₂Cl₂ (1:1). The eluant wascollected and concentrated under reduced pressure to give 0.32 g of thecrude product as an oil. The crude product was purified by silica gelchromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3mmol, 48%) of (S)-tert-butyl4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF3; R¹═R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68(br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96 (d, J=15.3 Hz,1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH⁺=443.7, 445.7;M⁺−56=388.0. HPLC R_(t) (A)=6.99 min.

Method CF, Step 4.

(S)-tert-butyl4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate(CF3; R¹═R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) wastreated with 1 mL of 30% TFA/CH₂Cl₂ at RT for 30 min. The volatiles wereremoved in vacuo. The residue was redissolved in acetonitrile (5 mL) andevaporated again to afford 17 mg of the crude product as a yellow solid.The crude product was purified via reverse phase HPLC to provide 10 mg(60%) of(S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one(CF4; R¹═R⁶=Me, R²¹=3-chloro-6-hydroxyphenyl) as a white solid. ¹HNMR(CDCl₃, 300 MHz): δ 11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m,3H), 3.68 (brs, 1H), 5.18 (brs, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s,3H), 2.95 (d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH⁺=344.1. HPLC(A) R_(t)=5.07 min.

Method CG

Method CG, Step 1;

A solution of CG1 (R²¹=Br, 12.29 g, 45 mmol) and NaOH (1.93 g, 49 mmol)in MeOH (70 mL) and water (10 mL) was refluxed for 3 h. After removal ofMeOH under vacuum, the aqueous residue was adjusted to pH 3 and theresulting solid filtered off, dried under vacuum to give CG2 (R²¹=Br,11.41 g, 98%). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (m, 1H), 8.27 (m, 1H),3.90 (s, 3H).

Method CG, Step 2;

A mixture of CG2 (R²¹=Br, 11.41 g, 44 mmol), EDCl (8.6 g, 45 mmol),dipropylamine (6.2 mL, 44.8 mmol), HOBt (6.0 g, 44.4 mmol) and NEt₃ (10mL, 72 mmol) in CH₂Cl₂ (100 mL) was stirred at RT for 48 h. The reactionwas washed with sat. NaHCO₃, water (1×), NH₄Cl (1×), water (1×), brine(1×), dried over MgSO₄, filtered and concentrated under vacuum. Theresulting material was subjected to silica gel chromatography (0%>40%EtOAc/hexanes) to give CG3 (R²¹=Br, R¹⁵═R¹⁶═Pr, 3.62 g, 24%).

Method CG, Step 3;

A mixture of CG3 (R²¹=Br, R¹⁵═R¹⁶═Pr, 3.6 g, 10.5 mmol), HN(Me)SO₂Me(1.4 mL, 16.3 mmol), Pd(OAc)₂ (355 mg, 1.58 mmol), Xantphos (1.41 g,2.44 mmol), Cs₂CO₃ (5.17 g, 15.8 mmol) in toluene (40 mL) was degassedunder a stream of N₂ for 10 min, then heated at 95° C. for 18 h. Thereaction was cooled to RT, filtered through celite, and the filtratepartitioned between EtOAc and water. The organic layer was washed withwater (1×), brine (1×), dried over MgSO₄, filtered, and evaporated undervacuum. The resulting residue was subjected twice to silica gelchromatography (0%>3% MeOH/CH₂Cl₂) to give CG4 (R²¹═N(Me)SO₂Me,R¹⁵═R¹⁶═Pr, 2.65 g, 68%).

Method CG, Step 4;

LiBH₄ (2 M THF, 8 mL, 16 mmol) was added to a solution of CG4(R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr, 2.65 g, 7.15 mmol) in THF (40 mL) at 0° C.After 18 h at RT, the reaction was quenched with 1 M HCl and extractedwith EtOAc. The organic layer was washed with brine (1×), dried overMgSO₄, filtered, and evaporated under vacuum. The resulting residue wassubjected to silica gel chromatography (0%>5% MeOH/CH₂Cl₂) to give CG5(R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr, 1.77 g, 72%).

Method CG, Step 5;

A mixture of CG5 (R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶=Pr, 1.77 g, 5.17 mmol), sodiumazide (404 mg, 6.21 mmol), and PPh₃ (2.85 g, 10.87 mmol) in CCl₄ (5 mL)and DMF (20 mL) was stirred at 90° C. for 5 h, then at RT for 18 h. Thereaction was stirred with water (10 mL) for 10 min, then diluted withEt₂O. The organic layer was triturated with water, filtered, dried overMgSO₄, and evaporated under vacuum. The resulting material was directlyused in the next step (azide reduction).

Method CG, Step 6;

The product from method CG, step 5 was dissolved in EtOH (5 mL) andstirred in the presence of 10% Pd/carbon under an atmosphere of hydrogen(50 psi) for 18 h at RT. The reaction mixture was passed through aPTFE-filter, and the filtrate evaporated under reduced pressure. Theresulting material was subjected to preparative thin layerchromatography (5% MeOH/CH₂Cl₂) to give CG6 (R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr,130 mg, 7.5% from CG5).

Method CG, Step 7;

A mixture of CG6 (R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr, 130 mg, 0.38 mmol),1,3-di(tert-butoxycarbonyl)-2-methylisothiourea (110 mg, 0.38 mmol),NEt₃ (55 μL, 0.38 mmol) in DMF (1.5 mL) was stirred at RT for 48 h.After removal of the volatiles in vacuo, the resulting material wassubjected to preparative thin layer chromatography (5% MeOH/CH₂Cl₂ aseluent). The resulting intermediate (140 mg, 0.24 mmol) was treated with50% TFA/CH₂Cl₂ at RT for 3 h, followed by removal of all volatiles undervacuum to give CG7 (R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr, 140 mg, 74% from CG6).

Method CG, Step 8;

A mixture of CG7 (R²¹═N(Me)SO₂Me, R¹⁵═R¹⁶═Pr, 120 mg, 0.24 mmol), benzil(50 mg, 0.24 mmol) and NEt₃ (134 μL, 0.96 mmol) in EtOH (5 mL) washeated at 100° C. for 18 h. After evaporating all volatiles, the residuewas partitioned between water and CH₂Cl₂. The organic layer was washedwith brine (1×), dried over MgSO₄, filtered and evaporated. Theresulting material was subjected to preparative thin layerchromatography (10% MeOH/CH₂Cl₂ as eluent) to give CG8 (R²¹═N(Me)SO₂Me,R¹⁵═R¹⁶═Pr, R³═R⁴=Ph, 69 mg, 50%) as the formate salt. ¹H NMR (400 MHz,CDCl₃) δ 7.10-7.40 (m, 13H), 4.72 (m, 2H), 3.34 (m, 2H), 3.08 (s, 3H),3.00 (m, 2H), 2.60 (s, 3 H), 1.59 (m, 2H), 1.39 (m, 2 H), 0.92 (m, 3 H),0.64 (m, 3 H); LCMS: 576.3 (M+H).

Method CH

A solution of 0.35 mL of 1 M BBr₃ in DCM (0.35 mmole) was added dropwiseto a solution of CH1 (52 mg, 0.11 mole) in 1.5 mL anhydrous DCM in icebath. The reaction solution was stirred in ice bath for 10 min. and 2hrs at RT. The reaction was quenched with 5 mL MeOH in ice bath. Afterconcentration the crude was purified on C18 reverse phase column to giveCH2 (37.3 mg, 67. % yield) as a formate.

Method CI

A solution of CI1 (20 mg as a formate; 0.042 mmole) in 4 mL of DCM wastreated with mCPBA (0.42 mmole) at RT for 2 hrs. The crude mixture waspurified on C18 reverse phase column to give compound CI2.

Method CJ

To a solution of CJ1 (R¹═R⁶=Me; 324 mg, 0.87 mmole) in 2.5 mL CHCl₃ and2.5 mL HOAC in ice bath was added NBS (312 mg, 1.75 mmole) and thereaction mixture was stirred at RT. Upon reaction completion, the crudemixture was diluted with DCM, and washed with saturated aqueous Na₂S₂O₃,aqueous NaHCO₃ and brine. The crude was purified on flash column to givea product which was treated with 50% TFA in DCM to give CJ2 (R¹═R⁶=Me220 mg, 56. % yield) after evaporation.

Method CK

Method CK, Step 1;

Similar to a literature procedure (Moloney et al., J. Med. Chem. 1997,2347-2362), methyl bromomethylbenzoate (7.00 g, 30.5 mmol) was added toa suspension of CK1 (R³═R⁴=Ph, 7.00 g, 27.8 mmol) and K₂CO₃ (3.85 g,27.8 mmol) in DMF (50 mL) at RT. After 18 h, the reaction mixture wasdiluted with water and extracted with CH₂Cl₂ (3×). The combined organiclayers were washed with NaHCO₃ (1×), water (3×), dried over MgSO₄,filtered and concentrated under vacuum to give compound CK2 (12.7 g,100%)

Method CK, Step 2;

Compound CK3 was obtained from CK2 using method BK, step 3.

Method CK, Step 3;

CK3 (1.18 g, 2.83 mmol) in THF (15 mL) and 2 N LiOH (4 mL, 8 mmol) wasstirred overnight at RT. The mixture was quenched with 6 N HCl (2 mL, 12mmol) and then partitioned between water and EtOAc. The dried EtOAclayer was concentrated in vacuo and the residue subjected toreverse-phase HPLC (gradient from 10%→95% CH₃CN/H₂O with 0.1% HCO₂H, 30mL/min flow rate on a preparative C18 reverse-phase column) to affordCK4.

Method CK, Step 4;

Compounds CK5 were obtained from CK4 using method G, step 2.

Method CK, Step 5;

Compounds CK6 were obtained from CK5 using method A, step 3.

Method CL

Method CL, Step 1;

CL2 was obtained from CL1 (3-chlorophenyl boronic acid) following methodAW.

Method CL, Step 2;

Trimethylsilyidiazomethane (2 M hexanes, 2.5 mL, 5.0 mmol) was added toa solution of LDA (freshly prepared from DIPA and ^(n)BuLi) in THF at−78° C. After 30 min at −78° C., a solution of aldehyde CL2 (900 mg,4.13 mmol) in THF (5 mL) was added and the reaction slowly warmed to RTover 3 h. The reaction was quenched with water, then extracted with Et₂O(2×100 mL). The combined organic layers were washed with brine (1×),dried over MgSO₄, filtered, and evaporated under vacuum. The resultingmaterial was subjected to silica gel chromatography (100% hexanes) togive CL3 (752 mg, 86%). ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.65 (m, 8H),3.08 (s, 1H).

Method CL, Step 3;

A mixture of CL3 (202 mg, 0.95 mmol), aryl bromide (Ar=3,5-pyrimidinyl,181 mg, 1.14 mmol), Pd(dba)₂ (27 mg. 47.5 μmol), PPh₃ (25 mg, 95 μmol),CuI (18 mg, 95 μmol) and DIPA (400 μL, 285 μmol) in DMF (2 mL) wasdegassed for 10 min under a stream of N₂, then heated at 100° C. for 30min in a Smith Synthesizer microwave. The reaction was cooled to RT,filtered and diluted with EtOAc. The organic layer was washed with water(1×), brine (1×), dried over MgSO₄, filtered, and evaporated undervacuum. The resulting material was subjected to silica gelchromatography (0→20% EtOAc/hexanes) to give CL4 (R³=3,5-pyrimidinyl,220 mg, 80%).

Method CL, Step 4;

A mixture of CL4 (R³=3,5-pyrimidinyl, 210 mg, 0.72 mmol), KMnO₄ (297 mg,1.88 mmol), tetrabutylammonium bromide (TBAB, 55 mg, 0.17 mmol) in AcOH(263 μL) and CH₂Cl₂ (5 mL) was stirred for 3 h at RT. The reactionmixture was filtered through a plug of silica gel, eluting with MeOH,and the filtrate was concentrated under vacuum. The residue wassubjected to preparative thin layer chromatography (5% MeOH/DCM) to giveCL5 (R³=3,5-pyrimidinyl, 154 mg, 66%).

Method CL, Step 5;

Diketone CL5 was converted into CL6 as described in Method CG, step 8.LCMS (CL6, R³=3,5-pyrimidinyl): 378.2 (M+H).

Method CM

Method CM, Step 1

To a round bottom flask were added CM1 (R¹=Me, R³=Ph; 500 mg, 1.22mmol), methanol (20 mL) and 10% Pd/C (200 mg). The mixture washydrogenated by a hydrogen balloon for 3 hour 40 min at stirring. Afterfiltration, the concentrated residue was purified by Analogix flashcolumn chromatography (EtOAc/Hexane=0%-50%) to produce CM2 (R¹=Me,R³=Ph; 443 mg, 92%) as white solid. Observed MW (M+H) 381.2. (400 MHz,CD₃OD): δ=9.13 (s, br, 1H), 7.36-7.26 (m, 5H), 7.09 (m, 1H), 6.68-6.57(m, 3H), 3.13 (s, 3H), 1.49 (s, 9H).

Method CN

To an Ace pressure tube were added CN1 (R³=phenyl; R¹=Me; 100 mg, 0.290mmol), bis(pinacolato)diboron (81.0 mg, 0.319 mmol), KOAc (85.0 mg, 0.87mmol), PdCl₂(dppf)₂.CH₂Cl₂ (24 mg, 0.029 mmol) and anhydrous DMSO (1.0mL). The reaction was then heated to 120° C. (oil bath temperature) atstirring for 2 hour 15 min. After cooling down to RT, the reaction wereadded 3,5-dibromo pyridine (206 mg, 0.87 mmol), anhydrous DMSO (1.0 mL)and 1M aq. K₂CO₃ (1.45 mL, 1.45 mmol). The reaction was then heated to120° C. at stirring for 45 min. After cooling down to RT, the reactionwas poured to cold water. The aqueous layer was extracted by DCM (3×50mL) and the combined organic layer was dried over Na₂SO₄. Theconcentrated residue was purified first by preparative TLC (7MNH₃/MeOH:DCM=1:10) and then preparative HPLC (reverse phase, C-18column, 0.1% HCOOH/CH₃CN: 0.1% HCOOH/H₂O=10%-100%) to afford the desiredproduct CN2 (formic acid salt; R³=phenyl; R¹=Me; R²¹=3′-(5-bromopyridyl;53.5 mg, 40%) as a white solid. Observed MW (M+H) 421.1. (400 MHz,CD₃OD): δ=8.83-8.50 (m, br. 2H), 8.21 (s, 1H), 7.65 (m, 2H), 7.50 (m,2H), 7.37 (m, 5H), 3.22 (s, 3H).

Method CO

A microwave tube was charged with CO1 (R¹=Me, R²═H; R³=cyclopropyl, n=0)(30 mg, 0.097 mmol), PS-Ph₃P—Pd (49 mg, 0.12 mmol), and R²¹SnBU₃(R²¹=2-pyrazinyl) (43 mg, 0.12 mmol) as a solution in 1 mL of PhCF₃. Thetube was sealed, and evacuated and back-filled with N₂ (5×). The mixturewas then exposed to microwave irradiation (110° C., 30 min). Theresulting mixture was filtered with copious MeOH washes. Concentrationof the filtrate gave a crude product that was subjected to RP-HPLC togive CO2 (R¹=Me, R²═H; R³=c-Pr, n=0, R²¹=2-pyrazinyl) as a formate salt(12 mg, 0.063 mmol, 35%). LCMS R_(t)=3.58 min, m/e=308.2 (M+H).

Method CP

Method CP; Step 1: 1,4,2-Diazaphospholidin-5-one,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP3)

Using methods similar to those described by I. V. Konovalova et al.(Zhurnal Obshchei Khimii, 50(7), 1653-1654), 1.0 equivalent ofphosphorisocyanatidous acid dimethyl ester (CP2), is added to a solutionof benzophenone imine (CP1) in toluene and the mixture is warmed toreflux for 4 h. Removal of solvent and purification by flashchromatography provides the title compound (CP3).

Method CP, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP4)

To a solution of CP3 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (CP4).

Method P1, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3,3-diphenyl-2-oxide (CP5)

Using a route similar to that described in Method A, step 3, CP4 is usedto prepare the title compound (CP5).

As a variant of Method CP, benzophenone imine (CP1) is treated with 1.0equivalent of phosphorisocyanatidous acid dimethyl ester[(CH₃O)₂P—N═C═S], giving directly CP4, which is coverted to CP5 asdescribed in Method CP, Step 3.

Method CQ

Method CQ, Step 1: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)], methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl [1-amino-1-(4-chloro)phenyl]ethylphosphonate(CQ1) in chloroform and the mixture is gradually warmed to reflux. After2 h at reflux, the mixture is cooled and solvent is removed byevaporation. Purification of the crude product by flash chromatographyprovides the title compound.

Method CQ, Step 2: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-methyl-3-(4-chloro)phenyl-2-oxide (CQ3)

Using a route similar to that described in Method A, step 3, CQ2 is usedto prepare the title compound.

Method CR

Method CR, Step 1: 1,4,2-Diazaphospholidin-5-one,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisocyanate (1.2 equivalents) is added toa solution of dimethyl [1-amino-1-(4-bromo)phenyl]ethylphosphonate (CR1)in chloroform and the mixture is gradually warmed to reflux. After 2 hat reflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provides thetitle compound (CR2).

Method CR, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR3)

To a solution of CR2 in toluene or xylene is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound.

Method CR, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-methyl-3-(4-bromo)phenyl-2-oxide (CR4)

Using a route similar to that described in Method A, step 3, CR3 is usedto prepare the title compound.

Method CS

Method CS, Step 1: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide(CS2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl[1-(4-methoxy)phenylmethylamino-2-(4-bromo)phenyl]ethylphosphonate (CS1)in chloroform and the mixture is gradually warmed to reflux. After 2 hat reflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provide thetitle compound.

Method CS, Step 2: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-4-(4-methoxy)phenylmethyl)-1-methyl-3-phenylmethyl-2-oxide(CS3)

Using a route similar to that described in Method A, step 3, CS2 is usedto prepare the title compound.

Method CS, Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-methyl-3-phenylmethyl-2-oxide (CS4)

A solution of CS3 in methanol is hydrogenated at 1 atm in the presenceof 5 mol % Pd/C, yielding the title compound after filtration andpurification by flash chromatography.

Method CT

Method CT, Step 1:Dimethyl-[(4-bromophenyl)-1-isothiocyanato]ethylphosphonate

To a mixture of CT1 in DCM and 0.1 N aqueous sodium bicarbonate (1.0equivalent) is added thiophosgene (1.5 equivalents), and the mixture isstirred for 4 h at RT. Water is added, and the organic phase is dried(MgSO₄), filtered and concentrated to give the product CT2 which is usedwithout purification.

Method CT, Step 2: 1,4,2-Diazaphospholidin-5-thione,2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT3)

To a solution of CT2 in acetonitrile is added ethylamine (2 equivalents)and diisopropylethylamine (2 equivalents) and the solution is slowlywarmed to reflux for 2 h. After removal of solvent, the product ispurified by flash chromatography to give the title product.

Method CT Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-ethyl-3-(4-bromo)phenyl-2-oxide (CT4)

Using a route similar to that described in Method A, step 3, CT3 is usedto prepare the title compound.

Method CU

Method CU, Step 1: 1,5,2-Diazaphosphorine-6(1H)-thione,1-methyl-2-methoxy-3-phenyl-2-oxide (CU2)

Using an approach similar to that described by R. Merten et al. [(Chem.Ber., 102, 2143 (1969)), methylisothiocyanate (1.2 equivalents) is addedto a solution of dimethyl (2-amino-1-phenyl)ethylphosphonate (CU1) inchloroform and the mixture is gradually warmed to reflux. After 2 h atreflux, the mixture is cooled and solvent is removed by evaporation.Purification of the crude product by flash chromatography provides thetitle compound.

Method CU, Step 2: 1,5,2-Diazaphosphorine-6(1H)-imine,1-methyl-2-methoxy-3-phenyl-2-oxide (CU3)

Using a route similar to that described in Method A, step 3, CU2 is usedto prepare the title compound.

Method CV

Method CV, Step 1: Dimethyl (2-isothiocyanato-1-phenyl)ethylphosphonate(CV2)

To a mixture of CV1 in methylene chloride and 0.1 N aqueous sodiumbicarbonate (1.0 equivalent) is added thiophosgene (1.5 equivalents),and the mixture is stirred for 4 h at RT. Water is added, and theorganic phase is dried (MgSO₄), filtered and concentrated to give theproduct which is used without purification.

Method CV, Step 2: 1,5,2-Diazaphosphorine-6(1H)-thione,1-cyclopropyl-2-methoxy-3-phenyl-2-oxide (CV3)

To a solution of CV2 in acetonitrile is added cyclopropylamine (2equivalents) and diisopropylethylamine (2 equivalents) and the solutionis heated at reflux for 2 h. After removal of solvent, the product ispurified by flash chromatography to give the title product.

Method CV Step 3: 1,4,2-Diazaphospholidin-5-imine,2-methoxy-1-cyclopropyl-3-(4-bromo)phenyl-2-oxide (CV4)

Using a route similar to that described in Method A, step 3, CV3 is usedto prepare the title compound.

Method CW

Method CW; Step 1: Boc-1,5,2-diazaphosphorine-5-imine,2-methoxy-1-methyl-4-(3-arylphenyl)-2-oxides (CW2)

Reaction of tert-butyl methylcarbamothioylcarbamate with CW1 (R⁶=Me)using EDCl and DIEA in DMF affords CW2 (R⁶=Me) after purification.

Method CW; Step 2: 1,5,2-Diazaphosphorine-5-imine,2-methoxy-1-methyl-4-(3-(m-cyanophenyl)phenyl)-2-oxides (CW3)

Following the procedure of Sauer, D. R. et al, Org. Lett., 2004, 6,2793-2796, Suzuki reaction of CW2 (R⁶=Me) with aryl boronic acids usingpolymer-support Pd catalysts such as Fibre Cat or PS—PPh3-Pd undermicrowave heating conditions provides CW3 (R⁶=Me and R²¹=m-CN-Ph) of theinvention after subsequent Boc-deprotection.

Method CX

Method CX, Step 1,(S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid

To a solution of (S)-tert-butyl4-(furan-2-yl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamateCX1 (R⁶=Me) (1.12 g, 3.64 mmol, prepared using Method CF) in DCM (7 mL)was added MeCN (7 mL) and H₂O (10.5 mL), followed by RuCl₃.H₂O (7.6 mg,0.036 mmol, 1 mol %), and NaIO₄ (11.6 g, 54.2 mmol, 15 eq). The mixturewas stirred at RT for 2 h. The mixture was diluted with DCM (100 mL) andthe organic layer was separated, dried (Na₂SO₄), and concentrated togive 0.90 g (86%) of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid CX2 (R⁶=Me) as a brown solid. ¹H NMR (CD₃OD): δ 3.17 (s, 3H), 3.02(m, 2H), 1.63 (s, 9H), 1.57 (s, 3H).

Method CX, Step 2,(6S)-2-Imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one(CX3)

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid (CX2, R⁶=Me, 0.035 g, 0.12 mmol) in DMF (0.24 mL) was added TBTU(0.040 mg, 0.12 mmol, 1 eq), HOBt (0.0035 mg, 0.024 mmol, 0.2 eq), andDIEA (0.107 mL, 0.60 mmol, 5 eq). The mixture was stirred at RT for 10min and then N′-hydroxy-3-(trifluoromethyl)benzamidine (0.028 mg, 0.13mmol, 1.1 eq) was added. After stirring for another 2 h, the reactionmixture was diluted with EtOAc (20 mL), washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The crude residuewas dissolved in THF (0.4 mL) and then TBAF (1 M in THF, 0.099 mL, 0.9eq) was added. The mixture was stirred at RT for 2 h. EtOAc (20 mL) wasadded to the reaction mixture, which was washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The residue wastreated with 30% TFA/DCM (1 mL) at RT for 1. The reaction mixture wasconcentrated in vacuo and the crude product was purified on reversephase HPLC (B) to give 0.015 g (26%) of(6S)-2-imino-3,6-dimethyl-6-(3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-tetrahydropyrimidin-4(1H)-one(CX3; R⁶=Me, R⁷=3-(3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)) asa white solid. ¹H NMR (CD₃OD): δ 8.40 (m, 2H), 8.04 (d, 1H, J=6.9 Hz),7.90 (t, 1H, J=8.1 Hz), 3.81 (m, 2H), 3.39 (s, 3H), 1.82 (s, 3H). MS(ESI): MH⁺=354.2, HPLC (A) R_(t)=6.234 min.

Method CY

(S)-2-(tert-Butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylicacid CX2 (R⁶=Me) (0.357 g, 1.25 mmol) in 1:5 MeOH/toluene (3 mL) wasadded TMSCHN₂ (2M in hexane, 1.9 mL, 3.8 mmol, 3 eq). The mixture wasstirred at RT for 2 h. The mixture was concentrated in vacuo to give0.37 g (100%) of (S)-methyl2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylateas a brown solid. ¹H NMR (CDCl₃): δ 8.80 (s, 1H), 3.70 (s, 3H), 3.14 (s,1H), 2.79 (s, 2H), 1.53 (s, 9H), 1.50 (s, 3H).

To a solution of (S)-methyl2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate(0.074 g, 0.25 mmol) in EtOH (0.5 mL) was added NH₂NH₂ (0.023 mL, 0.75mmol, 3 eq) and the mixture was stirred at RT for 4 h. The mixture wasconcentrated in vacuo to give 0.074 g (100%) of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1, R⁶=Me) as a yellow solid. ¹H NMR (CDCl₃) δ 8.95 (s, 1H), 3.11 (s,3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).

Method CZ

3-(5-((S)-2-Imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1; R⁶=Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et₃N(0.035 mL, 0.24 mmol, 2 eq) followed by 3-cyanobenzoyl chloride (0.027g, 0.16 mmol, 1.3 eq). The mixture was stirred at RT for 6 h. Themixture was diluted with DCM (20 mL), washed with H₂O (10 mL) andsaturated brine (10 mL), and concentrated in vacuo. The residue was thentreated with TsCl (0.035 g, 0.18 mmol, 1.5 eq), Et₃N (0.046 mL, 0.31mmol, 2.6 eq), and DMAP (0.002 g, 0.016 mmol, 0.13 eq) in DCM (0.25 mL)at RT for 16 h. The mixture was diluted with DCM (20 mL), washed withH₂O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. Theresidue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixturewas concentrated in vacuo and the residue was purified on reverse phaseHPLC (B) to give 0.006 g (12%) of3-(5-((S)-2-imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrileas a white solid (CZ1; R⁶=Me). ¹HNMR (CD₃OD, 300 MHz): δ 8.49 (m, 2H),8.12 (d, 1H), 7.92 (t, 1H), 3.75 (m, 2H), 3.36 (s, 3H), 1.82 (s, 3H). MS(ESI): MH⁺=311.2, HPLC (A) R_(t)=4.175 min.

Method DA

(S)-6-(5-(3-Chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one

To a solution of(S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide(CY1, R⁶=Me, 0.030 g, 0.10 mmol) in DCM (0.25 mL) was added3-chlorophenylisocyanate (0.015 mL, 0.20 mmol, 2 eq). The mixture wasstirred at RT for 3 h and volatiles were then removed in vacuo. Theresidue was treated with TsCl (0.020 g, 0.10 mmol, 1 eq), Et₃N (0.083mL, 0.60 mmol, 6 eq), and DMAP (0.002 g, 0.016 mmol, 0.16 eq) in DCM(0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL),washed with H₂O (10 mL) and saturated brine (10 mL), and concentrated invacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h.The mixture was concentrated in vacuo and the residue was purified onreverse phase HPLC (B) to give 0.006 g (10%) of(S)-6-(5-(3-chlorophenylamino)-1,3,4-oxadiazol-2-yl)-2-imino-3,6-dimethyl-tetrahydropyrimidin-4(1H)-one(DA1; R⁶=Me). ¹HNMR (CD₃OD, 300 MHz): δ 7.78 (t, 1H), 7.47 (m, 2H), 7.17(dt, 1H), 3.53 (m, 2H), 3.36 (s, 3H), 1.78 (s, 3H). MS (ESI): MH⁺=335.3,HPLC (A) R_(t)=5.710 min.

Method DB

Method DB, Step 1; (1-(3-Bromophenyl)ethylidene)cyanamide (DB1, R⁴=Me)

Following the procedure of Cuccia, S. J.; Fleming, L. B.; France, D. J.Synth. Comm. 2002, 32 (19), 3011-3018: 3-Bromoacetophenone (2.0 g, 10mmol, 1 eq), was dissolved in 20 mL DCM. A 1.0 N solution of titaniumtetrachloride in DCM (20 mL, 20 mmol, 2 eq) was added dropwise over 15min and the resulting mixture was stirred at 25° C. for 1 h.Bis-trimethylsilylcarbodiimide (5.0 mL, 22 mmol, 2.2 eq) in 5 mL of DCMwas added over 15 min and the reaction was stirred for 16 h under argon.The reaction was poured onto 200 mL of an ice/water mixture andextracted with 3×200 mL of DCM. The combined organic phase was driedover MgSO₄, filtered, and concentrated to give 2.3 g (100%) of(1-(3-bromophenyl)ethylidene)cyanamide (DB1, R⁴=Me) as a white solid: ¹HNMR (CDCl₃) δ 8.16 (t, J=1.8 Hz, 1H), 7.94 (dd, J=1.7, 1.1 Hz, 1H), 7.76(dd, J=1.7, 1.1 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 2.82 (s, 3H).

Method DB, Step 2;5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R⁴=Me)

To a solution of the HCl salt of methylhydroxylamine (0.19 g, 2.2 mmol,1 eq) in ethanol (25 mL) at 25° C. was added a 21% solution of NaOEt inethanol (0.75 mL, 2.0 mmol, 0.9 eq) followed by(1-(3-bromophenyl)ethylidene) cyanamide (0.50 g, 2.2 mmol, 1 eq). Afterstirring at 25° C. for 10 min, the solvent was removed in vacuo. Theresidue was redissolved in CH₂Cl₂ (25 mL), the mixture was filtered, andthe solvent was removed in vacuo to give 0.5 g (83%) of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (DB2, R¹=Me,R⁴=Me) as a colorless oil: ¹H NMR (CDCl₃) δ 7.63 (t, J=1.8 Hz, 1H), 7.52(dd, J=2.0, 1.1 Hz, 1H), 7.38 (dd, J=2.0, 1.1 Hz, 1H), 7.29 (t, J=7.9Hz, 1H), 3.28 (s, 3H), 1.88 (s, 3H). MS (ESI) m/e 270.0, 272.0 (M+H)⁺.

Method DB, Step 3;5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

To a solution of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine (25 mg, 0.093mmol) and 3-chlorophenyl boronic acid (17 mg, 0.11 mmol) in ethanol (1mL) was added a 1 M aqueous solution of K₂CO₃ (0.22 mL, 0.22 mmol) andPS—PPh₃-Pd (46 mg, 0.0046 mmol). The sample was heated in an EmrysOptimizer Microwave at 110° C. for 10 min. The resin was filtered offand rinsed alternately three times with CH₂Cl₂ (5 mL) and CH₃OH (5 mL).The combined filtrates were concentrated and the residue was purified byreverse phase prep-HPLC to give 12.3 mg (44%) of5-(3-(3′-chlorophenyl)-phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine(DB3; R¹=Me, R⁴=Me, R²¹=3-chlorophenyl) as a colorless oil: ¹H NMR(CDCl₃) δ 7.69 (s, 1H), 7.58 (m, 2H), 7.49 (m, 3H), 7.37 (m, 2H), 3.29(s, 3H), 1.94 (s, 3H). MS (ESI) m/e 302.0, 304.0 (M⁺H)⁺.

Using a similar procedure, the following compounds were also prepared.

5-(3-(3-Methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.72 (s, 1H), 7.62 (dt, 1H), 7.49 (m, 2H), 7.38 (t,J=8.2 Hz, 1H), 7.20 (m, 1H), 7.14 (t, 1H), 6.93 (m, 1H), 3.88 (s, 3H),3.27 (s, 3H), 1.95 (s, 3H). MS m/e 298.1 (M⁺H)

5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ7.67 (s, 1H), 7.57 (m, 1H), 7.45 (m, 2H), 6.92 (m, 3H),3.82 (s, 3H), 3.77 (s, 3H), 3.27 (s, 3H), 1.95 (s, 3H). MS m/e 328.1(M⁺H)

5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ7.71 (s, 1H), 7.60 (m, 1H), 7.50 (m, 2H), 7.41 (m, 2H),7.31 (m, 1H), 7.08 (m, 1H), 3.29 (s, 3H), 1.94 (s, 3H). MS m/e 286.0(M⁺H)

5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.70 (s, 1H), 7.59 (m, 1H), 7.55 (m, 1H), 7.50 (m, 2H),7.46-7.48 (m, 2H), 7.26 (m, 1H), 3.29 (s, 3H), 1.95 (s, 3H). MS m/e352.1 (M⁺H)

5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CD₃OD) δ 9.17 (s, 1H), 8.84 (m, 2H), 8.08 (m, 1H), 7.99 (s, 1H),7.88 (m, 1H), 7.72 (m, 2H), 3.37 (s, 3H), 2.00 (s, 3H). MS m/e 269.1(M⁺H)

5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.66 (s, 1H), 7.54 (m, 1H), 7.52 (m, 2H), 7.47 (m, 2H),7.38 (m, 1H), 3.30 (s, 3H), 1.94 (s, 3H). MS m/e 336.1 (M⁺H)

5-(3-(2-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.59 (m, 1H), 7.50 (m, 4H), 7.34 (m, 3H), 3.28 (s, 3H),1.95 (s, 3H). MS m/e 302.1 (M⁺H)

5-(3-(3-Chloro-4-fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazolidin-3-imine

¹H NMR (CDCl₃) δ 7.65 (m, 2H), 7.48-7.54 (m, 4H), 7.22 (m, 1H), 3.30 (s,3H), 1.94 (s, 3H). MS m/e 320.1 (M⁺H)

Method DC

Method DC, Step 1, 5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione

A mixture of 3-bromoacetophenone (10 g, 50 mmol), KCN (8.16 g, 130 mmol,2.5 eq) and (NH₄)₂CO₃ (21.7 g, 225 mmol, 4.5 eq) in EtOH/H₂O (1:1, 110mL) was heated at 60° C. for 16 h. The reaction mixture was cooled to 0°C. The resulting precipitate was filtered, washed with water, hexane,and then dried to give 12.6 g (93%) of5-(3-bromophenyl)-5-methylimidazolidine-2,4-dione as an off-white solid(DC1; R⁶=Me). ¹H NMR (CD₃OD) δ 7.64 (s, 1H), 7.45 (t, J=9.7 Hz, 2H),7.26 (t, J=7.6 Hz, 1H), 1.68 (s, 3H).

Method DC, Step 2, 2-Amino-2-(3-bromophenyl)propanoic acid

5-(3-Bromophenyl)-5-methylimidazolidine-2,4-dione (DC1; R⁶=Me) (1.5 g,5.6 mmol) was dissolved in 15 mL of 1N KOH, heated to 185° C. in amicrowave reactor (Emrys Optimizer) for 2 h. Afterward, the mixture wascarefully acidified using conc. HCl to pH ˜2. The mixture was extractedonce with Et₂O (20 mL). The aqueous layer was concentrated in vacuo togive 1.6 g (100%) of 2-amino-2-(3-bromophenyl)-2-propanoic acid (DC2;R⁶=Me) as an off white solid. ¹H NMR (CD₃OD) δ 7.75 (t, J=2.0, 1H), 7.66(m, 1H), 7.56 (m, 1H), 7.45 (t, J=8.1 Hz, 1H), 1.99 (s, 3H).

Method DC, Step 3, 2-(3-Bromophenyl)-2-(tert-butoxycarbonyl)propanoicacid

To a solution of 2-amino-2-(3-bromophenyl)-propanoic acid (DC2; R⁶=Me)(10.5 g, 43 mmol) in 1N KOH (105 mL) and dioxane (70 mL) at 0° C. wasadded (Boc)₂O (20.6 g, 95 mmol, 2.2 eq). The mixture was stirred at RTfor 16 h. The reaction mixture was concentrated to 100 mL. EtOAc (100mL) was added and the mixture was cooled to 0° C. After acidifying with2N KHSO₄ to pH 2-3, the aqueous layer was extracted with EtOAc (3×50mL). The combined EtOAc layer was washed with H₂O (2×50 mL), dried(Na₂SO₄), and concentrated to give 11.7 g (79%) of2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoic acid as a whitesolid. ¹H NMR (CDCl₃) δ 7.61 (s, 1H), 7.41 (m, 2H), 7.24 (m, 1H), 1.98(s, 3H), 1.44 (s, 9H).

To a solution of 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoic acid(11.3 g, 32.8 mmol) in MeOH (35 mL) was added toluene (175 mL) followedby TMSCHN₂ (2M in hexane, 44 mL, 98 mmol, 3 eq). The mixture was stirredat RT for 16 h. Solvents were evaporated and the residue waschromatographed on silica by eluting with EtOAc/hexanes to give 11.8 g(100%) of methyl 2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate asa yellow oil. ¹H NMR (CDCl₃) δ 7.59 (t, J=1.8 Hz, 1H), 7.36-7.44 (m,2H), 7.21 (t, J=8.0 Hz, 1H), 5.92 (s, 1H), 3.70 (s, 3H), 1.97 (s, 3H),1.36 (br s, 9H).

To a solution of methyl2-(3-bromophenyl)-2-(tert-butoxycarbonyl)propanoate (11.8 g, 33 mmol) inTHF (150 mL) at −78° C. was added LAH powder (3.1 g, 82.0 mmol, 2.5 eq).The mixture was stirred at −78° C. and allowed to warm to RT over 16 h.The mixture was cooled to 0° C. and the reaction was quenched by slowlyadding 3 mL of H₂O. The mixture was diluted with DCM (500 mL) followedby the addition of 1N NaOH (6 mL) and H₂O (9 mL). After stirring at 0°C. for 30 min, the mixture was filtered and the filtrate wasconcentrated to give 10 g (95%) of tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R⁶=Me) as acolorless oil. ¹H NMR (CDCl₃) δ 7.49 (t, J=1.8 Hz, 1H), 7.35-7.39 (m,1H), 7.27-7.30 (m, 1H), 7.21 (t, J=7.8 Hz, 1H), 3.72 (m, 2H), 1.57 (s,3H), 1.41 (br s, 9H).

Method DC, Step 4;3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

To a solution of SOCl₂ (5.7 mL, 2.5 eq) in dry CH₃CN (37 mL) under argonwas cooled to −40° C. was added tert-butyl2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R⁴=Me) (10.3 g, 31mmol) in dry CH₃CN (27 mL) was added dropwise, followed by the additionof dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowedto warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc(30 mL) was added and the precipitate was filtered off. The filtrate wasconcentrated in vacuo to give 10.4 g (89%) of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxideas a colorless oil. ¹H NMR (CDCl₃) δ 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53(m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s,9H).

To a solution of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide(10.4 g, 28 mmol) in CH₃CN (50 mL) at 0° C. was added RuO₄ (0.5% instabilized aq., 50 mg, 0.1% by weight) in H₂O (10 mL) and NaIO₄ (8.9 g,41.5 mmol, 1.5 eq) in H₂O (35 mL). The mixture was stirred at RT for 2h. The mixture was partitioned between Et₂O (200 mL) and H₂O (50 mL).The organic layer was separated and the aqueous layer was extracted withEt₂O (3×50 mL). The combined organic layer was dried (Na₂SO₄), andconcentrated to give 10.8 g (100%) of3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC4; R⁶=Me) as a white solid (˜10.8 g, yield: 100%). ¹H NMR (CDCl₃) δ7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t,J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39(s, 9H).

Method DC, Step 5;3-Allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide

3-(tert-Butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC4; R⁶=Me) (10.8 g, 28 mmol) was dissolved in 25% TFA in DCM (40 mL, 5eq) and the mixture was left standing at RT for 3 h. The mixture wasconcentrated in vacuo to give 7.3 g (91%) of4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide as ayellow oil. ¹H NMR (CDCl₃) δ 7.59 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H),7.39-7.42 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 4.59 (m, 2H), 1.82 (s, 3H).

To a solution of4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (7.3 g,25 mmol) in DCM (77 mL) was added allyl iodide (9.1 mL, 100 mmol, 4 eq),followed by BnBu₃NCl (0.39 g, 1.3 mmol) and 40% NaOH (28 mL). Themixture was stirred at RT for 16 h. The organic layer was separated andthe solvent was evaporated. Silica gel chromatography using 5-20%EtOAc/hexanes gave 8.3 g (100%) of3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC5; R⁶=Me) as a colorless oil. ¹H NMR (CDCl₃) δ 7.64 (t, J=1.8 Hz,1H), 7.46-7.54 (m, 2H), 7.31 (t, J=8.0 Hz, 1H), 5.77-5.89 (m, 1H),5.19-5.33 (m, 2H), 4.38 (dd, J1=8.7 Hz, J2=23.7 Hz, 2H), 3.46-3.68 (m,2H), 1.83 (s, 3H).

Method DC, Step 6; N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine

To a suspension of NaH (60%, 0.14 g, 1.5 eq) in 0.5 mL of anhydrous DMFwas added tert-butyl hydroxy(methyl)carbamate (0.52 g, 1.5 eq) in 1.5 mLof DMF. After stirring at RT for 15 min, a solution of3-allyl-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide(DC5; R⁶=Me) (0.78 g, 2.3 mmol) in 6 mL of anhydrous DMF was addeddropwise. The mixture was stirred at RT for 16 h. The mixture waspartitioned between EtOAc (10 mL) and 1N HCl (3 mL). The organic layerwas separated and the aqueous layer was extracted with EtOAc (3×5 mL).The combined organic layer was dried over Na₂SO₄ and concentrated togive 0.45 g (41%) of a product which was used without purification.

To a solution of the above product (3.86 g, 8.1 mmol) in THF (30 mL) wasadded a pre-stirred (15 min) mixture of Pd₂(dba)₃ (0.51 g, 0.41 mmol)and 1,4-bis(diphenylphosphio)butane (0.25 g, 0.41 mmol) in THF (5 mL),followed by thiosalicyliacid (2.2 g, 1.2 eq). The mixture was stirred atRT for 16 h. Solvent was evaporated and the residue was chromatographedon silica by eluting with 50% EtOAc/hexanes to give 1.3 g (37%) productas a oil which was dissolved in 4M HCl/dioxane (11 mL) and the mixturewas stirred at RT for 2 h. Solvent was evaporated in vacuo and theresidue was diluted with CHCl₃ (10 mL) followed by treatment with 1NNaOH tol pH˜12. The organic layer was separated and the aqueous layerwas extracted with CHCl₃ (3×10 mL). The combined organic layer was dried(Na₂SO₄) and concentrated to give 0.56 g (76%) ofN-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine (DC6; R⁶=Me, R¹=Me)as a colorless oil. ¹H NMR (CDCl₃) δ 7.74 (t, J=1.8 Hz, 1H), 7.41-7.50(m, 2H), 7.26 (t, J=8.0 Hz, 1H), 3.85 (dd, J1=9.6 Hz, J2=28.8 Hz, 2H),2.72 (s, 3H), 1.48 (s, 3H).

Method DC, Step 7;5-(3-Bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

To a solution of N-(2-(3-bromophenyl)-2-amino)prop-1-oxy)-methylamine(DC6; R⁶=Me, R¹=Me) (0.76 g, 2.9 mmol) in EtOH (10 mL) was added BrCN(0.46 g, 4.4 mmol, 1.5 eq). After stirring at RT for 16 h, the mixturewas concentrated. The residue was redissolved in CHCl₃ (20 mL) andwashed with 2N NaOH (10 mL). The aqueous layer was extracted with CHCl₃(3×10 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated to give 0.82 g (100%) of5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC7; R⁶=Me,R¹=Me) as a light yellow oil. ¹H NMR (CDCl₃) δ 10.59 (s, 1H), 8.12 (brs,1H), 7.46 (m, 2H), 7.29 (m, 2H), 4.14 (dd, J1=11.5 Hz, J2=57.7 Hz, 2H),3.39 (s, 3H), 1.69 (s, 3H).

Method DC, Step 8;5-(3-(3-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

A mixture of 5-(3-bromophenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine(DC7; R⁶=Me, R¹=Me) (0.025 g, 0.088 mmol, 1 eq), 3-cyanophenylboronicacid (0.019 g, 0.13 mmol, 1.5 eq), FibreCat (40 mg), anhydrous ethanol(1.5 mL), and a 1N K₂CO₃ aqueous solution (0.12 mL, 0.12 mmol, 1.4 eq)in a microwave vial was heated in a microwave reactor (Emrys Optimizer)at 110° C. for 15 min. The mixture was filtered, concentrated andpurified by prep HPLC (B) to give 0.012 g (44%) of5-(3-(3-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine (DC8;R⁶=Me, R¹=Me, R²¹=3-cyanophenyl) as a white solid. ¹H NMR (CDCl₃) δ10.67 (s, 1H), 8.05 (br s, 1H), 7.85 (m, 2H), 7.50-7.66 (m, 5H), 7.35(m, 1H), 4.22 (dd, J1=11.8 Hz, J2=48.6 Hz, 2H), 3.40 (s, 3H), 1.76 (s,3H). MS m/e 307.3 (M⁺H)

Using a similar procedure, the following compounds were also prepared:

5-(3-(3-Pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.85 (s, 1H), 9.13 (s, 1H), 8.76 (m, 1H), 8.65 (m,1H), 7.92 (m, 2H), 7.81 (s, 1H), 7.60 (m, 2H), 7.44 (m, 1H), 4.26 (dd,J1=11.8 Hz, J2=37.4 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 283.2(M⁺H)

5-(3-(5-Pyrimidyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.77 (brs, 1H), 10.42 (s, 1H), 9.26 (s, 1H), 9.07 (s,1H), 7.84 (br s, 1H), 7.57-7.63 (m, 3H), 7.46 (m, 1H), 4.23 (dd, J1=11.5Hz, J2=45.9 Hz, 2H), 3.41 (s, 3H), 1.77 (s, 3H). MS m/e 284.2 (M⁺H)

5-(3-(3-Chlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.63 (s, 1H), 8.00 (br s, 1H), 7.46-7.55 (m, 5H),7.31-7.7.40 (m, 3H), 4.20 (dd, J1=11.5 Hz, J2=54.4 Hz, 2H), 3.39 (s,3H), 1.76 (s, 3H). MS m/e 316.2 (M⁺H)

5-(3-(3-Trifluoromethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.72 (s, 1H), 8.03 (br s, 1H), 7.55 (m, 1H), 7.51 (m,2H), 7.46 (m, 2H), 7.41 (m, 1H), 7.32-7.34 (dt, J1=1.6 Hz, J2=7.2 Hz,1H), 7.21-7.23 (m, 1H), 4.21 (dd, J1=11.8 Hz, J2=53.0 Hz, 2H), 3.39 (s,3H), 1.76 (s, 3H). MS m/e 366.2 (M⁺H)

5-(3-(3-Toluyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.61 (s, 1H), 8.07 (br s, 1H), 7.53 (m, 2H), 7.45 (m,1H), 7.33-7.37 (m, 3H), 7.28-7.32 (m, 1H), 7.17-7.19 (m, 1H), 4.20 (dd,J1=11.8 Hz, J2=58.2 Hz, 2H), 3.38 (s, 3H), 2.42 (s, 3H), 1.76 (s, 3H).MS m/e 296.4 (M⁺H)

5-(3-(3,5-Dichlorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.71 (s, 1H), 8.06 (br s, 1H), 7.47 (m, 3H), 7.43 (m,2H), 7.35 (m, 2H), 4.20 (dd, J1=11.7 Hz, J2=54.9 Hz, 2H), 3.40 (s, 3H),1.76 (s, 3H). MS m/e 350.2 (M⁺H)

5-(3-(2-Fluoro-5-cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.50 (s, 1H), 7.86 (br s, 1H), 7.77 (dd, J1=2.1 Hz,J2=6.9 Hz, 1H), 7.65 (m, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 7.27 (t, J=5.0Hz, 2H), 4.20 (dd, J1=12.0 Hz, J2=50.4 Hz, 2H), 3.40 (s, 3H), 1.76 (s,3H). MS m/e 325.1 (M⁺H)

5-(3-(2-Fluoro-5-methoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.53 (s, 1H), 7.94 (br s, 1H), 7.47 (m, 3H), 7.37 (m,1H), 7.07 (t, J=9.5 Hz, 1H), 6.93 (m, 1H), 6.86 (m, 1H), 4.19 (dd,J1=11.7 Hz, J2=58.5 Hz, 2H), 3.82 (s, 3H), 3.38 (s, 3H), 1.75 (s, 3H).MS m/e 330.1 (M⁺H)

5-(3-(3-Dimethylaminocarbonylphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.58 (s, 1H), 7.95 (br s, 1H), 7.26-7.65 (m, 8H), 4.20(dd, J1=11.5 Hz, J2=54.7 Hz, 2H), 3.38 (s, 3H), 3.14 (s, 3H), 3.02 (s,3H), 1.75 (s, 3H). MS m/e 353.2 (M⁺H)

5-(3-(2,5-Dimethoxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.50 (s, 1H), 7.99 (br s, 1H), 7.40-7.50 (m, 3H),7.29-7.33 (m, 1H), 6.84-6.94 (m, 3H), 4.18 (dd, J1=11.5 Hz, J2=65.4 Hz,2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.37 (s, 3H), 1.74 (s, 3H). MS m/e342.2 (M⁺H)

5-(3-(3-Hydroxyphenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 7.39-7.54 (m, 3H), 7.21-7.30 (m, 2H),7.10-7.12 (m, 2H), 6.82-6.84 (m, 1H), 5.83 (br s, 2H), 4.15 (dd, J1=11.5Hz, J2=35.7 Hz, 2H), 3.36 (s, 3H), 1.74 (s, 3H). MS m/e 298.3 (M⁺H)

5-(3-(3-Fluorophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.77 (s, 1H), 8.15 (s, 1H), 7.25-7.56 (m, 7H),7.01-7.08 (m, 1H), 4.20 (dd, J1=11.5 Hz, J2=53.0 Hz, 2H), 3.40 (s, 3H),1.76 (s, 3H). MS m/e 300.2 (M⁺H)

5-(3-(4-Cyanophenyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.67 (s, 1H), 8.01 (br s, 1H), 7.74 (s, 4H), 7.63 (s,1H), 7.48-7.56 (m, 2H), 7.33-7.35 (m, 1H), 4.23 (dd, J1=11.5 Hz, J2=47.2Hz, 2H), 3.40 (s, 3H), 1.76 (s, 3H). MS m/e 307.2 (M⁺H)

5-(3-(4-Methoxy-3-pyridyl)phenyl)-2,5-dimethyl-1,2,4-oxadiazinan-3-imine

¹H NMR (CDCl₃) δ 10.55 (s, 1H), 8.74 (d, J=6.0 Hz, 1H), 8.64 (s, 1H),7.83 (br s, 1H), 7.49-7.53 (m, 3H), 7.37-7.42 (m, 2H), 4.20 (dd, J1=11.5Hz, J2=49.4 Hz, 2H), 4.11 (s, 3H), 3.39 (s, 3H), 1.76 (s, 3H). MS m/e313.2 (M⁺H)

Method DD

Method DD, Step 1;

To a 10 mL MeOH solution of DD1 (R³═R⁶═H, R⁷=Me, 1 g) was addedp-methoxybenzaldehyde (1 eq) and 4 A molecular sieves (4 g). Thesolution was stirred overnight before sodium borohydride (1 eq) wasadded and reaction stirred for 1 h. The reaction mixture was filted andsolvent evaporated. The residue was chromatographed using MeOH/DCM toafford compound DD2 (R³═R⁶═H, R⁷=Me).

Method DD, Step 2;

Procedure similar to Method CF, step 2 was used for generation of DD3(R¹=Me, R³═R⁶═H, R⁷=Me,).

Method DD, Step 3;

Procedure similar to Method CF, step 3 was used for generation of DD4(R¹=Me, R³═R⁶═H, R⁷=Me) from DD3

Method DD, Step 4;

Compound DD4 was hydrogenated using Pd(OH)₂/C in Methanol. After removalof the catalyst and solvent the crude product was treated with 20% TFAin DCM to give product DD5 (R¹=Me, R³═R⁶═H, R⁷=Me) after purification.

Method DE

Method DE, Step 1:5-(4-Chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine1,1-dioxide

2-(4-Chlorophenyl)ethenesulfonyl chloride DE1 is treated with 1.2equivalents of S-methyl isothiourea hemisulfate and a slight excess of1N NaOH in acetone. After 12 h at RT the mixture is concentrated invacuo and the precipitate collected to give the title compound.

Method DE, Step 2:N-(2-(4-Chlorophenyl)ethene-1-sulfonyl)-S-methylisothiourea

Using a method similar to that described by K. Hasegawa and S. Hirooka(Bull. Chem. Soc. Jap., 1972, 45, 1893),N-(2-(4-chlorophenyl)ethylene-1-sulfonyl)thiourea DE2 in DMF is treatedwith 1N NaOH (2.4 equivalents) and dimethyl sulfate (1.2 equivalents) at0-10° C. After 3 h at RT, the reaction mixture is poured into ice water.The precipitate is collected, washed with water and dried to give thetitle compound DE3.

Method DE, Step 2:5-(4-Chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by K. Hasegawa and S. Hirooka(Bull. Chem. Soc. Jap., 1972, 45, 1893),5-(4-chlorophenyl)-3-methylsulfanyl-5,6-dihydro-4H-[1,2,4]thiadiazine1,1-dioxide DE2 in acetone is treated with 1N NaOH and the mixture isrefluxed for 2 h. The acetone is evaporated and the mixture is acidifiedwith conc. HCl to afford the title compound DE3.

Method DE, Step 3:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-one

Using a method similar to that described by A. Etienne et al. (Bull.Soc. Chim. Fr., 1974, 1395)5-(4-chlorophenyl)-1,1-dioxo-[1,2,4]thiadiazinan-3-one DE3 is treatedwith sodium methoxide (1 equivalent) in methanol. Add methyl iodide (1.2equivalent) in DMF and allow to stir for 12 h. Pour the mixture into icewater and collect the precipitate of the title compound DE4.

Method DE, Step 4:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-thione

To a solution of DE4 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (DE5).

Method DE, Step 5:5-(4-Chlorophenyl)-2-methyl-1,1-dioxo-[1,2,4]thiadiazinan-3-ylideneamine

Using a route similar to that described in Method A, step 3, DE5 is usedto prepare the title compound (DE6).

As a variant of this method, DE2 is treated with ammonia and theresultant product is treated with sodium hydride and methyl iodide inDMF to give the product DE6

Method DF

Method DF, Step 1: 2-Hydrazinocarbonylpropane-2-sulfonic acidcyclohexylamide

Using a method similar to that described by S. Paik and E. H. White(Tetrahedron, 1996, 52, 5303), 2-cyclohexylsulfamoyl-2-methylpropionicacid ethyl ester DF1 (which is prepared by the method of A. De Blic etal. (Synthesis, 1982, 281)) in ethanol is treated with 1.2 equivalent of95% hydrazine under N₂ and the mixture is allowed to stand at RT for 12h. The reaction mixture is concentrated to give the title compound DF2which is used directly in Step 2.

Method DF, Step 2:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-one-1,1-dioxide

A solution of DF2 in CH₂Cl₂ is refluxed under a N₂ for 10 h. The solventis removed in vacuo and the crude product is purified by flashchromatography to provide the title compound DF3.

Method DF, Step 3:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-thione-1,1-dioxide

To a solution of DF3 in toluene (or xylene) is added Lawesson's reagent(1.2 equivalents), and the mixture is stirred at reflux for 2 h. Themixture is cooled and poured into cold water. The organic phase is dried(MgSO₄) and filtered, and solvent is removed. The crude product ispurified by flash chromatography to provide the title compound (DF4).

Method DF, Step 4:2-Cyclohexyl-5,5-dimethyl-1,2,4-thiadiazolidin-3-imine-1,1-dioxide

Using a route similar to that described in Method A, step 3, DF4 is usedto prepare the title compound (DF5).

Method DG

Method DG, Step 1,

To a stirred solution of the iminopyrimidinone DG1 (R¹=Me, W=—(CO)—,R⁷=Me, R⁶=4-(m-cyanophenyl)thien-2-yl; 200 mg, 0.47 mmol, 1 equiv) in 1mL THF at −20° C. in a reaction vial protected with nitrogen was slowlyadded 1M LiHMDS in THF (1 mL, 1.04 mmol, 2.2 equiv). After 20 min at−20° C., a solution of zinc chloride (142 mg, 1.04 mmol, 2.2 equiv) inTHF (0.71 mL) was added. After 30 min at −20° C., the solution wastransferred to a mixture of2-(Dicyclohexylphosphino)-2-(N,N-dimethylamino)biphenyl (DavePhos) (14mg, 35.3 μmol, 7.5 mol %), Pd₂ (dba)₃ (22 mg, 23.6 μmol, 5.0 mol %) andBr—R3 (R3=Ph, 50 μL, 0.47 mmol, 1 equiv) in THF (0.5 mL). The reactionmixture was heated to 65° C. overnight, cooled to rt, quenched withsaturated aqueous NH₄Cl and extracted with EtOAc. The organic phase waswashed with aqueous NaHCO₃, brine and dried over anhydrous Na₂SO₄. Thecrude was purified on a flash column with EtOAc/hexane from 0 to 50% in25 min. The purified material was treated with 25% TFA in DCM for 30min. After evaporation of TFA in vacuum, the residue was dissolved inDCM and neutralized with aqueous NaHCO₃. The organic phase was washedwith brine and dried over anhydrous Na₂SO₄. Solvent was evaporated invacuum to give 78 mg (41.3%) of DG2 (R¹=Me, W=—(CO)—, R⁷=Me,R⁶=4-(m-cyanophenyl)thien-2-yl, R³=Ph) as free base. ¹H NMR (CDCl₃) δ:7.74 (m, 1H), 7.70-7.67 (m, 1H), 7.57-7.52 (m, 1H), 7.50-7.44 (m, 1H),7.37-7.30 (m, 4H), 7.18-7.16 (m, 2H), 6.93 (m, 1H), 4.10 (s, 1H), 3.30(s, 3H), 1.45 (s, 3H). MS (LCMS): Calcd for C₂₃H₂₁N₄OS (M+H⁺): 401.14.Found: 401.2.

The following table contains example compounds which were synthesizedwith procedure(s) similar to methods listed in the corresponding columnand whose LCMS data (obs. mass) (M+1) are also listed.

Obs. # Compounds Method Mass 1491

CF 297 1492

CF 333.9 1493

CF 329.9 1494

CF 367.9 1495

AW 281 1496

CF 306 1497

AB 307 1498

CF 314 1499

CF 318 1500

CF 325 1501

CF 325 1502

CF 330 1503

CF 336 1504

CF 336 1505

AB 340 1506

CE 342 1507

CF 343 1508

CF 344 1509

CF 344 1510

CF 344 1511

AB 354 1512

A 354 1513

CF 358 1514

CF 358 1515

BS 358 1516

A 364 1517

A 366 1518

A 366 1519

A 368 1520

A 370 1521

AB 374 1522

A 380 1523

A 382 1524

A 382 1525

BS 383 1526

CF 384 1527

A 384 1528

A 384 1529

A 384 1530

A 384 1531

A 396 1532

A 396 1533

A 397 1534

A 398 1535

A 398 1536

A 398 1537

A 398 1538

A 398 1539

A 400 1540

A 402 1541

AB 404 1542

A 406 1543

A 406 1544

BS 408 1545

A 410 1546

A 410 1547

A 411 1548

A 412 1549

A 412 1550

A 414 1551

CE 415 1552

A 416 1553

A 417 1554

A 417 1555

A 419 1556

A 420 1557

A 421 1558

A 422 1559

A 422 1560

A 422 1561

A 423 1562

A 423 1563

CE 424 1564

A 425 1565

A 426 1566

A 426 1567

A 426 1568

A 431 1569

A 431 1570

A 431 1571

A 433 1572

A 434 1573

A 437 1574

A 439 1575

A 465 1576

CG 470 1577

CG 470 1578

CG 470 1579

CG 470 1580

CE 474 1581

CG 484 1582

CG 484 1583

BR 489 1584

CF 274.1 1585

AW 311.1 1586

AB 312.1 1587

AB 319.1 1588

CF 320.1 1589

CF 325.1 1590

AB 328.1 1591

AW 332.1 1592

CE 333.1 1593

CF 336.1 1594

AW 337.1 1595

CF 337.1 1596

CF 337.1 1597

CF 337.1 1598

AB 338.1 1599

AB 338.1 1600

CE 338.1 1601

CF 339.1 1602

CE 339.1 1603

AB 342.1 1604

AW 343.1 1605

AB 345.1 1606

AB 346.1 1607

AB 350.1 1608

CF 350.1 1609

AW 356.1 1610

AW 357.1 1611

AW 359.1 1612

AB 362.1 1613

CE 364.1 1614

CE 365.1 1615

AW 367.1 1616

AW 368.1 1617

AW 372.1 1618

CF 373.1 1619

AB 378.1 1620

AW 378.1 1621

CF 379.1 1622

CF 384.1 1623

BQ 386.1 1624

BQ 387.1 1625

AB 388.1 1626

CO 399.1 1627

BW 412.1 1628

BW 412.1 1629

CE 414.1 1630

BQ 419.1 1631

AW 421.1 1632

AM 425.1 1633

AW 425.1 1634

BW 426.1 1635

AW 436.1 1636

BQ 439.1 1637

BQ 440.1 1638

BQ 453.1 1639

CH 455.1 1640

BW 463.1 1641

Q 468.1 1642

BS 478.1 1643

BS 478.1 1644

BS 484.1 1645

BS 484.1 1646

BQ 492.1 1647

BW 492.1 1648

BW 495.1 1649

BW 496.1 1650

Q 560.1 1651

AW 569.1 1652

BW 573.1 1653

AW 470.1 1654

AW 307.2 1655

AW 308.2 1656

CP 308.2 1657

AW 315.2 1658

AW 321.2 1659

CO 321.2 1660

AW 325.2 1661

AW 326.2 1662

AW 328.2 1663

AW 331.2 1664

CE 335.2 1665

AW 336.2 1666

AW 337.2 1667

CF 339.2 1668

AW 340.2 1669

CO 341.2 1670

AW 342.2 1671

AW 346.2 1672

AW 350.2 1673

CJ 352.2 1674

AW 354.2 1675

AW 355.2 1676

CE 359.2 1677

AW 361.2 1678

AW 361.2 1679

AW 361.2 1680

AW 362.2 1681

AW 368.2 1682

AW 372.2 1683

AW 374.2 1684

BQ 375.2 1685

CL 377.2 1686

BK 377.2 1687

AW 377.2 1688

CQ 378.2 1689

AW 383.2 1690

CO 385.2 1691

BQ 386.2 1692

AW 406.2 1693

CL 408.2 1694

BS 409.2 1695

BW 412.2 1696

BW 413.2 1697

BW 413.2 1698

BS 420.2 1699

R 425.2 1700

R 425.2 1701

BQ 429.2 1702

BQ 430.2 1703

R 434.2 1704

R 434.2 1705

BW 437.2 1706

AW 439.2 1707

BQ 440.2 1708

BQ 441.2 1709

BQ 441.2 1710

BW 442.2 1711

BQ 445.2 1712

BQ 446.2 1713

R 446.2 1714

R 446.2 1715

BS 448.2 1716

R 448.2 1717

BQ 450.2 1718

BQ 450.2 1719

BW 451.2 1720

CI 452.2 1721

BQ 454.2 1722

BQ 454.2 1723

AW 419.2 1724

AW 423.2 1725

AW 430.2 1726

AW 431.2 1727

AW 435.2 1728

CK 439.2 1729

AW 441.2 1730

AW 450.3 1731

CK 453.3 1732

CK 453.3 1733

AW 453.3 1734

CK 455.3 1735

L 467.3 1736

L 467.3 1737

CK 469.3 1738

CK 481.3 1739

CK 483.3 1740

CK 497.3 1741

CK 425.3 1742

BQ 515.3 1743

BQ 516.3 1744

BQ 519.3 1745

BQ 522.3 1746

BQ 525.3 1747

BQ 532.3 1748

CG 576.3 1749

BQ 455.3 1750

BW 456.3 1751

BQ 456.3 1752

BQ 456.3 1753

BS 456.3 1754

BQ 456.3 1755

AW 456.3 1756

BQ 458.3 1757

BQ 458.3 1758

BQ 458.3 1759

BQ 458.3 1760

BS 460.3 1761

R 460.3 1762

BW 462.3 1763

BW 462.3 1764

BW 463.3 1765

BQ 464.3 1766

BQ 464.3 1767

BW 465.3 1768

BQ 467.3 1769

Q 467.3 1770

BS 468.3 1771

BW 468.3 1772

Q 468.3 1773

BQ 469.3 1774

BQ 469.3 1775

CG 469.3 1776

BQ 470.3 1777

BQ 470.3 1778

BS 472.3 1779

BQ 473.3 1780

BQ 473.3 1781

BS 473.3 1782

Q 473.3 1783

AW 473.3 1784

BQ 474.3 1785

BQ 478.3 1786

AZ 478.3 1787

AZ 478.3 1788

BS 479.3 1789

Q 481.3 1790

BS 482.3 1791

Q 482.3 1792

R 482.3 1793

R 482.3 1794

482.3 1795

R 482.3 1796

BS 484.3 1797

R 486.3 1798

R 486.3 1799

CK 487.3 1800

BS 488.3 1801

BS 488.3 1802

BS 488.3 1803

BQ 488.3 1804

BW 488.3 1805

R 488.3 1806

BQ 489.3 1807

BQ 489.3 1807

AW 489.3 1809

BQ 492.3 1810

Q 493.3 1811

BS 497.3 1812

CG 497.3 1813

BS 498.3 1814

R 498.3 1815

498.3 1816

498.3 1817

R 498.3 1818

R 502.3 1819

R 502.3 1820

BS 504.3 1821

BS 504.3 1822

BQ 504.3 1823

BQ 508.3 1824

CF 334.0, 331.1 1825

CF 342.1, 336.0 1826

CF 352.0, 344.1 1827

CF 358.1, 353.9 1828

CF 358.1, 360.1 1829

CF 363.1, 365.1 1830

CF 367.9, 369.9 1831

A 501.1, 499 1832

CE 309

The following compounds with their observed molecular masses (M+1) arelisted in the table below.

Obs. # Structure Mass 1890

376.2 1891

376.2 1892

376.2 1893

376.2 1894

376.2 1895

498.3 1896

350.2 1897

484.3 1898

388.2 1899

416.1 1900

1901

457.4 1902

354.3 1903

500.3 1904

397.1 1905

336.8 1906

364.4 1907

399.2 1908

321.1 1909

461.3 1910

1911

476.3 1912

561.3 1913

332.2 1914

385.2 1915

308.0 1916

460.3 1917

468.3 1918

493.3 1919

399.2 1920

466.3 1921

358.1 1922

428.3 1923

1924

308.2 1925

360.2 1926

341.2 1927

338.3 1928

1929

448.3 1930

262.1 1931

489.3 1932

459.9 1933

1934

446.0 1935

435.2 1936

400.2 1937

479.3 1938

480.3 1939

392.0 1940

374.2 1941

380.0 1942

314.2 1943

476.3 1944

358.2 1945

373.2 1946

312.2 1947

393.2 1948

468.3 1949

319.0 1950

503.3 1951

362.0 1952

1953

314.2 1954

392.2 1955

451.3 1956

533.3 1957

373.3 1958

350.2 1959

472.3 1960

340.4 1961

455.3 1962

332.2 1963

505.3 1964

409.2 1965

300.2 1966

340.1 1967

410.2 1968

363.2 1969

441.2 1970

375.2 1971

412.2 1972

418.2 1973

434.1 1974

329.2 1975

441.2 1976

568.3 1977

267.2 1978

455.3 1979

327.9 1980

1981

344.1 1982

396.1 1983

358.0 1984

443.2 1985

404.2 1986

314.2 1987

303.2 1988

375.2 1989

410.4 1990

384.2 1991

314.2 1992

349.0 1993

379.9 1994

408.2 1995

470.3 1996

379.3 1997

449.3 1998

385.2 1999

254.1 2000

321.3 2001

337.1 2002

338.1 2003

420.2 2004

427.2 2005

490.9 2006

457.4 2007

461.3 2008

2009

336.2 2010

506.3 2011

484.3 2012

352.0 2013

387.0 2014

384.2 2015

523.3 2016

353.2 2017

419.1 2018

343.2 2019

475.3 2020

364.1 2021

413.2 2022

472.3 2023

2024

479.3 2025

357.2 2026

434.2 2027

432.2 2028

400.1 2029

384.2 2030

448.3 2031

448.3 2032

295.1 2033

392.2 2034

456.3 2035

421.0 2036

343.2 2037

343.0 2038

344.2 2039

303.0 2040

250.0 2041

469.3 2042

2043

373.2 2044

381.2 2045

471.3 2046

356.2 2047

299.2 2048

333.0 2049

475.3 2050

352.2 2051

2052

531.3 2053

382.0 2054

372.2 2055

377.2 2056

402.2 2057

434.2 2058

448.3 2059

477.3 2060

366.2 2061

462.3 2062

435.2 2063

341.2 2064

489.3 2065

365.2 2066

357.2 2067

519.3 2068

338.2 2069

362.2 2070

442.2 2071

282.0 2072

443.2 2073

486.3 2074

413.2 2075

444.2 2076

503.3 2077

430.2 2078

429.2 2079

357.2 2080

326.0 2081

339.2 2082

335.2 2083

354.2 2084

442.2 2085

343.2 2086

434.0 2087

2088

460.3 2089

398.2 2090

2091

476.3 2092

376.2 2093

413.2 2094

432.2 2095

579.3 2096

388.2 2097

471.3 2098

435.2 2099

317.2 2100

357.2 2101

2102

416.2 2103

468.3 2104

2105

434.2 2106

398.2 2107

349.2 2108

381.2 2109

423.2 2110

486.3 2111

320.0 2112

350.2 2113

232.1 2114

360.2 2115

356.2 2116

366.2 2117

346.2 2118

375.2 2119

336.2 2120

393.0 2121

310.2 2122

339.2 2123

408.2 2124

479.3 2125

355.2 2126

397.2 2127

432.3 2128

337.2 2129

402.2 2130

359.2 2131

380.2 2132

352.1 2133

370.2 2134

314.2 2135

397.9 2136

408.2 2137

504.3 2138

347.1 2139

362.2 2140

326.3 2141

381.2 2142

320.1 2143

329.2 2144

471.3 2145

445.2 2146

321.2 2147

560.3 2148

255.0 2149

338.2 2150

474.3 2151

360.2 2152

371.2 2153

342.9 2154

560.3 2155

2156

374.8 2157

296.0 2158

391.2 2159

2160

441.9 2161

387.2 2162

330.2 2163

407.2 2164

408.2 2165

483.1 2166

386.2 2167

441.2 2168

519.3 2169

388.2 2170

298.2 2171

471.0 2172

409.2 2173

339.1 2174

368.2 2175

501.3 2176

388.2 2177

2178

2179

405.1 2180

331.2 2181

454.3 2182

479.3 2183

392.2 2184

379.1 2185

351.2 2186

482.3 2187

2188

319.0 2189

352.2 2190

2191

372.1 2192

449.3 2193

353.2 2194

379.3 2195

447.3 2196

2197

377.3 2198

372.2 2199

385.2 2200

433.2 2201

420.2 2202

350.2 2203

459.3 2204

363.0 2205

383.2 2206

431.9 2207

287.2 2208

402.9 2209

429.2 2210

365.2 2211

325.1 2212

461.3 2213

449.2 2214

310.2 2215

431.2 2216

336.2 2217

372.2 2218

2219

395.2 2220

484.3 2221

479.3 2222

360.2 2223

543.3 2224

411.2 2225

358.2 2226

286.2 2227

290.0 2228

386.1 2229

386.1 2230

2231

415.2 2232

456.3 2233

377.2 2234

447.3 2235

366.2 2236

340.2 2237

388.1 2238

417.2 2239

398.2 2240

471.3 2241

427.3 2242

312.2 2243

466.3 2244

218.1 2245

470.3 2246

373.2 2247

415.2 2248

400.0 2249

275.2 2250

466.0 2251

435.2 2252

371.2 2253

394.2 2254

449.3 2255

483.3 2256

495.3 2257

340.0 2258

413.2 2259

302.2 2260

350.2 2261

321.1 2262

455.3 2263

526.3 2264

477.3 2265

341.1 2266

316.2 2267

392.2 2268

301.0 2269

483.3 2270

2271

321.2 2272

448.3 2273

481.3 2274

257.1 2275

325.0 2276

250.3 2277

450.3 2278

316.2 2279

486.3 2280

464.3 2281

2282

369.2 2283

302.0 2284

362.2 2285

300.0 2286

462.3 2287

331.0 2288

535.3 2289

364.2 2290

305.1 2291

337.0 2292

376.2 2293

418.2

Obs. # Structure Mass 2294

345.3 2295

353.1 2296

375.2 2297

411.1 2298

2299

409.2 2300

310.2 2301

339.2 2302

394.2 2303

383.2 2304

356.2 2305

479.3 2306

269.2 2307

341.2 2308

439.2 2309

439.1 2310

410.2 2311

322.1 2312

401.0 2313

351.2 2314

439.2 2315

2316

420.2 2317

438.2 2318

2319

509.3 2320

425.2 2321

434.2 2322

390.2 2323

357.2 2324

467.3 2325

296.1 2326

310.2 2327

342.2 2328

331.3 2329

343.0 2330

2331

489.3 2332

332.2 2333

487.3 2334

411.0 2335

442.2 2336

356.2 2337

441.2 2338

496.3 2339

472.3 2340

425.2 2341

359.2 2342

379.0 2343

459.3 2344

435.2 2345

436.2 2346

390.2 2347

383.2 2348

281.1 2349

363.2 2350

359.2 2351

363.2 2352

418.2 2353

427.2 2354

450.9 2355

483.3 2356

415.2 2357

395.2 2358

466.3 2359

390.2 2360

460.3 2361

388.0 2362

486.3 2363

375.2 2364

445.2 2365

444.2 2366

392.2 2367

417.2 2368

326.2 2369

337.8 2370

418.2 2371

487.3 2372

2373

329.3 2374

493.3 2375

354.2 2376

368.2 2377

288.2 2378

429.2 2379

519.3 2380

354.2 2381

376.2 2382

274.2 2383

314.1 2384

388.2 2385

412.2 2386

351.2 2387

395.1 2388

372.2 2389

375.2 2390

411.9 2391

249.1 2392

442.2 2393

397.0 2394

327.3 2395

433.2 2396

420.2 2397

383.2 2398

378.2 2399

358.1 2400

460.3 2401

2402

491.3 2403

416.1 2404

465.3 2405

350.4 2406

457.3 2407

389.2 2408

386.2 2409

407.2 2410

2411

337.1 2412

329.1 2413

478.3 2414

413.0 2415

327.2 2416

2417

450.3 2418

2419

314.2 2420

405.2 2421

450.3 2422

396.1 2423

449.3 2424

2425

317.2 2426

472.3 2427

448.3 2428

342.2 2429

370.2 2430

2431

491.3 2432

2433

2434

344.2 2435

508.3 2436

390.2 2437

368.2 2438

370.2 2439

331.2 2440

427.2 2441

365.2 2442

419.2 2443

447.3 2444

436.2 2445

389.2 2446

341.2 2447

428.2 2448

377.2 2449

456.3 2450

387.4 2451

431.2 2452

307.2 2453

392.0 2454

467.3 2455

428.2 2456

407.4 2457

324.2 2458

451.3 2459

377.2 2460

318.2 2461

304.2 2462

2463

432.2 2464

515.3 2465

343.2 2466

427.0 2467

414.2 2468

501.3 2469

475.3 2470

401.2 2471

366.2 2472

312.1 2473

461.9 2474

335.2 2475

481.3 2476

304.2 2477

344.3 2478

393.2 2479

383.2 2480

508.9 2481

363.2 2482

405.2 2483

435.2 2484

319.0 2485

356.2 2486

395.1 2487

461.3 2488

406.2 2489

434.2 2490

467.3 2491

2492

469.4 2493

408.1 2494

446.2 2495

384.0 2496

380.2 2497

392.2 2498

2499

510.3 2500

469.3 2501

363.0 2502

375.1 2503

372.2 2504

236.0 2505

260.1 2506

417.2 2507

322.2 2508

512.3 2509

465.3 2510

454.3 2511

454.3 2512

427.2 2513

250.1 2514

2515

334.2 2516

358.2 2517

340.2 2518

334.1 2519

369.2 2520

2521

356.2 2522

393.2 2523

379.2 2524

406.0 2525

454.1 2526

413.2 2527

337.1 2528

461.3 2529

312.2 2530

371.2 2531

255.1 2532

359.2 2533

399.2 2534

420.2 2535

420.2 2536

455.3 2537

357.0 2538

367.2 2539

467.3 2540

441.2 2541

456.3 2542

395.1 2543

461.1 2544

319.2 2545

468.3 2546

511.1 2547

344.0 2548

484.3 2549

495.3 2550

486.3 2551

426.2 2552

283.0 2553

479.3 2554

351.2 2555

372.2 2556

340.1 2557

410.2 2558

359.2 2559

352.2 2560

432.2 2561

434.2 2562

390.2 2563

398.3 2564

563.0 2565

356.2 2566

394.0 2567

326.2 2568

335.2 2569

380.2 2570

498.3 2571

331.2 2572

434.2 2573

501.3 2574

418.2 2575

324.0 2576

455.3 2577

361.0 2578

489.3 2579

388.2 2580

389.2 2581

338.0 2582

338.1 2583

309.5 2584

2585

330.2 2586

430.0 2587

459.3 2588

403.2 2589

339.0 2590

2591

347.2 2592

344.1 2593

381.2 2594

391.2 2595

339.0 2596

383.2 2597

540.3 2598

359.2 2599

461.3 2600

453.3 2601

2602

433.2 2603

408.3 2604

311.2 2605

302.2 2606

340.2 2607

2608

466.3 2609

406.1 2610

386.2 2611

2612

402.2 2613

467.3 2614

410.0 2615

326.2 2616

445.2 2617

441.2 2618

458.3 2619

461.3 2620

443.2 2621

498.3 2622

299.1 2623

349.2 2624

387.4 2625

420.9 2626

403.8 2627

434.2 2628

419.2 2629

377.1 2630

456.3 2631

387.1 2632

2633

2634

384.2 2635

290.2 2636

310.0 2637

399.2 2638

431.2 2639

354.1 2640

313.2 2641

393.3 2642

424.2 2643

495.3 2644

326.1 2645

418.9 2646

302.9 2647

2648

2649

305.1 2650

485.1 2651

375.2 2652

351.2 2653

315.9 2654

2655

503.3 2656

2657

283.0 2658

2659

386.2 2660

351.2 2661

560.3 2662

502.3 2663

481.3 2664

428.2 2665

311.2 2666

403.8 2667

402.2 2668

2669

444.2 2670

366.2 2671

385.2 2672

497.3 2673

497.3 2674

381.2 2675

279.2 2676

444.2 2677

413.2 2678

323.2 2679

430.2 2680

325.1 2681

2682

457.3 2683

357.2 2684

479.1 2685

363.9 2686

485.3 2687

515.3 2688

341.0 2689

427.2 2690

364.2 2691

442.2 2692

390.2 2693

467.3 2694

452.3 2695

372.2 2696

356.2 2697

380.2 2698

271.2 2699

335.0 2700

279.2 2701

502.3 2702

170.0 2703

2704

356.2 2705

368.2 2706

435.2 2707

468.3 2708

438.2 2709

405.1 2710

339.2 2711

310.3 2712

336.2 2713

479.3 2714

330.2 2715

372.2 2716

322.2 2717

363.1 2718

368.2 2719

516.3 2720

468.3 2721

365.0 2722

298.1 2723

394.2 2724

254.0

Obs. # Structure Mass 2725

272.2 2726

357.1 2727

505.3 2728

463.3 2729

311.0 2730

456.3 2731

343.2 2732

483.3 2733

2734

2735

358.1 2736

466.3 2737

370.0 2738

225.1 2739

411.2 2740

505.3 2741

378.2 2742

2743

352.2 2744

420.2 2745

498.3 2746

490.3 2747

372.2 2748

447.3 2749

359.3 2750

486.3 2751

426.2 2752

323.2 2753

370.2 2754

2755

2756

408.2 2757

421.2 2758

421.0 2759

417.2 2760

311.2 2761

449.3 2762

326.2 2763

340.2 2764

345.2 2765

450.3 2766

380.2 2767

340.3 2768

375.2 2769

301.2 2770

336.2 2771

422.2 2772

348.2 2773

331.2 2774

429.2 2775

496.3 2776

380.2 2777

342.2 2778

343.2 2779

348.2 2780

427.2 2781

272.2 2782

376.2 2783

399.0 2784

403.9 2785

467.3 2786

328.1 2787

457.3 2788

451.3 2789

514.3 2790

462.3 2791

395.2 2792

445.2 2793

501.3 2794

378.2 2795

373.2 2796

369.2 2797

342.1 2798

339.2 2799

477.3 2800

375.2 2801

2802

378.0 2803

394.2 2804

400.2 2805

349.2 2806

446.3 2807

499.3 2808

491.3 2809

449.1 2810

468.3 2811

359.2 2812

311.0 2813

472.3 2814

481.3 2815

410.2 2816

394.2 2817

238.2 2818

326.2 2819

380.2 2820

438.2 2821

254.1 2822

458.8 2823

424.2 2824

349.2 2825

429.2 2826

2827

395.2 2828

392.2 2829

350.2 2830

363.2 2831

388.2 2832

531.3 2833

397.2 2834

379.1 2835

435.2 2836

327.3 2837

2838

418.2 2839

426.0 2840

462.3 2841

258.1 2842

343.0 2843

390.2 2844

345.1 2845

415.2 2846

372.2 2847

380.0 2848

480.3 2849

283.2 2850

370.2 2851

356.2 2852

2853

342.2 2854

456.3 2855

401.1 2856

452.3 2857

367.2 2858

364.2 2859

356.2 2860

435.2 2861

485.3 2862

451.3 2863

364.1 2864

341.2 2865

316.0 2866

250.3 2867

2868

340.2 2869

367.0 2870

2871

343.2 2872

421.2 2873

425.2 2874

438.2 2875

450.3 2876

461.3 2877

342.2 2878

497.3 2879

457.3 2880

428.2 2881

497.3 2882

2883

405.1 2884

475.3 2885

344.0 2886

483.3 2887

375.2 2888

467.3 2889

350.2 2890

2891

335.2 2892

342.2 2893

434.2 2894

384.2 2895

317.2 2896

393.2 2897

443.2 2898

444.0 2899

316.0 2900

379.2 2901

386.1 2902

258.0 2903

379.2 2904

394.2 2905

449.3 2906

427.2 2907

219.1 2908

410.2 2909

2910

2911

395.0 2912

490.3 2913

261.1 2914

394.2 2915

242.1 2916

377.2 2917

343.7 2918

468.3 2919

307.2 2920

390.2 2921

330.0 2922

555.3 2923

483.3 2924

394.2 2925

443.2 2926

340.2 2927

369.2 2928

443.2 2929

433.2 2930

454.3 2931

444.1 2932

436.2 2933

435.2 2934

471.3 2935

385.2 2936

358.2 2937

2938

451.3 2939

2940

355.1 2941

324.1 2942

372.2 2943

382.1 2944

372.1 2945

478.3 2946

515.3 2947

455.3 2948

407.1 2949

490.3 2950

423.0 2951

333.2 2952

258.1 2953

404.2 2954

449.3 2955

453.3 2956

489.3 2957

470.3 2958

376.2 2959

377.0 2960

392.0 2961

373.2 2962

309.0 2963

331.1 2964

400.2 2965

346.2 2966

364.1 2967

351.1 2968

339.3 2969

2970

355.0 2971

383.1 2972

429.2 2973

441.2 2974

442.2 2975

351.0 2976

349.2 2977

456.3 2978

2979

443.2 2980

333.1 2981

450.1 2982

359.0 2983

368.2 2984

352.2 2985

253.1 2986

453.3 2987

350.4 2988

392.2 2989

355.2 2990

432.1 2991

462.3 2992

399.2 2993

402.2 2994

305.1 2995

429.4 2996

337.2 2997

418.2 2998

460.3 2999

359.2 3000

296.1 3001

452.3 3002

405.1 3003

441.2 3004

349.2 3005

423.2 3006

3007

398.0 3008

3009

355.1 3010

458.3 3011

286.2 3012

493.3 3013

340.2 3014

343.0 3015

322.0 3016

441.2 3017

3018

428.2 3019

329.2 3020

340.2 3021

294.1 3022

479.3 3023

404.1 3024

489.3 3025

308.0 3026

447.3 3027

365.2 3028

407.2 3029

460.3 3030

449.3 3031

312.2 3032

406.2 3033

272.2 3034

601.3 3035

321.2 3036

404.9 3037

357.0 3038

311.2 3039

3040

292.2 3041

300.1 3042

344.2 3043

340.2 3044

387.2 3045

491.3 3046

322.2 3047

344.3 3048

476.3 3049

399.2 3050

438.1 3051

433.1 3052

3053

284.2 3054

388.2 3055

340.2 3056

289.0 3057

357.2 3058

441.2 3059

383.2 3060

285.2 3061

399.2 3062

459.3 3063

437.2 3064

378.2 3065

390.2 3066

376.2 3067

412.2 3068

360.2 3069

363.2 3070

448.3 3071

3072

434.1 3073

3074

374.8 3075

416.1 3076

496.3 3077

462.3 3078

3079

439.1 3080

340.2 3081

372.1 3082

368.2 3083

450.3 3084

401.9 3085

391.0 3086

515.3 3087

362.2 3088

346.1 3089

326.3 3090

341.2 3091

417.2 3092

375.1 3093

456.3 3094

460.3 3095

438.2 3096

447.3 3097

375.2 3098

252.0 3099

463.3 3100

469.3 3101

359.0 3102

387.2 3103

435.2 3104

470.3 3105

390.2 3106

354.2 3107

413.2 3108

376.2 3109

449.3 3110

451.1 3111

466.3 3112

372.2 3113

589.3 3114

368.0 3115

320.0 3116

3117

381.0 3118

3119

301.0 3120

368.2 3121

509.3 3122

364.2 3123

383.2 3124

425.2 3125

467.3 3126

363.2 3127

3128

306.2

Obs. # Structure Mass 3129

505.8 3130

351.2 3131

391.2 3132

336.2 3133

300.1 3134

418.2 3135

476.9 3136

514.3 3137

451.3 3138

461.3 3139

330.2 3140

467.3 3141

447.3 3142

3143

344.0 3144

371.2 3145

391.2 3146

341.2 3147

452.3 3148

314.2 3149

3150

484.3 3151

460.3 3152

434.2 3153

482.3 3154

408.2 3155

310.0 3156

340.2 3157

407.3 3158

373.2 3159

335.2 3160

487.3 3161

387.2 3162

449.3 3163

303.2 3164

3165

453.3 3166

385.3 3167

369.0 3168

476.3 3169

3170

350.2 3171

371.2 3172

3173

490.3 3174

457.4 3175

326.2 3176

441.2 3177

451.3 3178

403.2 3179

309.5 3180

483.3 3181

420.2 3182

3183

457.3 3184

315.2 3185

315.0 3186

307.0 3187

469.3 3188

3189

362.2 3190

3191

317.0 3192

391.2 3193

355.2 3194

328.3 3195

343.3 3196

345.1 3197

357.2 3198

456.3 3199

304.0 3200

417.2 3201

607.3 3202

348.2 3203

391.1 3204

368.2 3205

243.1 3206

428.2 3207

437.2 3208

457.3 3209

3210

459.3 3211

430.2 3212

371.2 3213

318.2 3214

358.2 3215

434.1 3216

334.2 3217

477.3 3218

384.1 3219

350.2 3220

477.3 3221

3222

326.2 3223

432.2 3224

439.0 3225

333.1 3226

457.2 3227

512.3 3228

479.3 3229

372.1 3230

376.2 3231

455.3 3232

428.2 3233

467.3 3234

348.2 3235

370.2 3236

459.3 3237

3238

399.2 3239

410.2 3240

378.2 3241

3242

349.2 3243

412.2 3244

312.2 3245

479.3 3246

469.3 3247

365.2 3248

375.3 3249

542.3 3250

448.3 3251

370.2 3252

329.0 3253

441.2 3254

358.0 3255

391.2 3256

257.1 3257

443.2 3258

204.1 3259

326.2 3260

365.2 3261

326.2 3262

365.2 3263

475.3 3264

299.1 3265

431.2 3266

309.2 3267

387.4 3268

431.2 3269

357.2 3270

486.3 3271

3272

380.2 3273

404.2 3274

432.2 3275

432.2 3276

379.1 3277

400.0 3278

409.2 3279

306.2 3280

347.0 3281

593.3 3282

3283

378.1 3284

409.2 3285

383.2 3286

396.2 3287

323.2 3288

309.4 3289

483.3 3290

372.0 3291

348.3 3292

328.1 3293

403.2 3294

460.0 3295

418.2 3296

481.3 3297

382.2 3298

432.2 3299

342.0 3300

415.2 3301

503.3 3302

347.2 3303

332.0 3304

325.2 3305

298.2 3306

358.2 3307

314.2 3308

435.2 3309

412.3 3310

360.2 3311

352.2 3312

308.2 3313

224.1 3314

390.1 3315

351.2 3316

335.2 3317

373.2 3318

457.3 3319

387.2 3320

465.3 3321

325.1 3322

354.2 3323

326.2 3324

342.1 3325

370.2 3326

475.3 3327

459.3 3328

450.3 3329

418.2 3330

463.3 3331

475.3 3332

515.3 3333

411.2 3334

384.1 3335

459.3 3336

421.2 3337

380.2 3338

378.2 3339

451.3 3340

597.3 3341

448.3 3342

315.3 3343

353.1 3344

3345

335.2 3346

448.3 3347

363.2 3348

483.3 3349

407.2 3350

453.3 3351

348.2 3352

411.2 3353

464.3 3354

463.3 3355

427.2 3356

463.3 3357

493.7 3358

3359

236.1 3360

441.2 3361

420.2 3362

343.0 3363

306.2 3364

324.2 3365

554.3 3366

424.2 3367

302.2 3368

392.2 3369

392.2 3370

421.0 3371

3372

391.1 3373

306.2 3374

3375

300.2 3376

521.3 3377

404.9 3378

374.0 3379

379.2 3380

422.2 3381

445.2 3382

434.3 3383

386.2 3384

461.3 3385

302.0 3386

404.4 3387

296.2 3388

442.2 3389

318.0 3390

340.2 3391

447.3 3392

310.1 3393

376.2 3394

335.9 3395

3396

344.2 3397

336.2 3398

456.3 3399

424.2 3400

413.2 3401

412.2 3402

364.2 3403

389.2 3404

356.0 3405

385.1 3406

462.3 3407

311.0 3408

418.2 3409

444.2 3410

365.0 3411

386.2 3412

390.2 3413

437.2 3414

337.2 3415

312.2 3416

367.2 3417

466.3 3418

349.2 3419

343.2 3420

285.9 3421

327.0 3422

427.2 3423

305.9 3424

3425

455.3 3426

368.2 3427

425.0 3428

390.2 3429

356.2 3430

410.2 3431

441.4 3432

326.3 3433

503.3 3434

385.2 3435

423.2 3436

465.3 3437

275.2 3438

378.0 3439

310.2 3440

3441

399.2 3442

498.3 3443

447.0 3444

394.2 3445

369.0 3446

313.2 3447

443.2 3448

309.4 3449

418.2 3450

439.2 3451

461.3 3452

281.1 3453

392.0 3454

275.1 3455

485.1 3456

3457

460.3 3458

434.1 3459

342.2 3460

555.3 3461

329.1 3462

354.0 3463

457.3 3464

455.3 3465

395.2 3466

3467

335.2 3468

412.3 3469

345.1 3470

3471

399.0 3472

456.3 3473

170.1 3474

463.3 3475

320.0 3476

336.2 3477

467.0 3478

353.2 3479

340.0 3480

446.0 3481

463.1 3482

486.3 3483

393.2 3484

315.4 3485

3486

317.2 3487

3488

367.2 3489

455.3 3490

268.3 3491

373.2 3492

518.3 3493

444.2 3494

3495

471.3 3496

321.1 3497

297.3 3498

326.2 3499

348.2 3500

3501

379.2 3502

470.3 3503

362.1 3504

372.1 3505

406.1 3506

377.2 3507

365.0 3508

368.2 3509

379.0 3510

224.0 3511

463.3 3512

449.1 3513

546.3 3514

382.2 3515

446.3 3516

463.3 3517

408.2 3518

448.3 3519

3520

470.3 3521

365.2 3522

468.3 3523

354.2 3524

318.2 3525

380.2 3526

352.2 3527

402.1 3528

452.2 3529

388.2 3530

373.2 3531

326.1 3532

509.3 3533

414.0 3534

476.3 3535

283.2 3536

323.2 3537

342.2 3538

502.3 3539

342.2 3540

3541

3542

393.3 3543

516.1 3544

491.3 3545

353.2 3546

324.0 3547

371.2 3548

374.2 3549

418.2 3550

415.2 3551

346.9 3552

360.2 3553

365.4 3554

364.2 3555

441.2 3556

436.0 3557

507.3 3558

337.2 3559

341.2

Obs. # Structure Mass 3560

3561

311.2 3562

410.0 3563

316.2 3564

3565

3566

3567

453.3 3568

449.3 3569

467.3 3570

325.0 3571

452.3 3572

254.1 3573

243.1 3574

388.2 3575

434.2 3576

378.0 3577

324.2 3578

313.1 3579

316.2 3580

224.1 3581

3582

495.3 3583

3584

373.2 3585

439.2 3586

365.2 3587

455.3 3588

356.1 3589

475.3 3590

380.2 3591

417.1 3592

427.2 3593

299.1 3594

366.2 3595

435.2 3596

348.2 3597

196.1 3598

378.2 3599

3600

401.2 3601

363.1 3602

426.2 3603

453.3 3604

353.4 3605

505.3 3606

484.3 3607

518.3 3608

446.0 3609

3610

393.2 3611

423.2 3612

379.2 3613

436.2 3614

401.2 3615

421.2 3616

418.2 3617

343.2 3618

388.2 3619

385.0 3620

362.1 3621

344.0 3622

294.1 3623

480.4 3624

366.1 3625

432.2 3626

365.2 3627

478.3 3628

417.2 3629

324.1 3630

3631

326.2 3632

351.0 3633

434.2 3634

443.2 3635

392.2 3636

457.4 3637

328.2 3638

466.3 3639

447.3 3640

396.2 3641

485.0 3642

3643

345.0 3644

302.0 3645

349.0 3646

413.2 3647

389.2 3648

425.2 3649

356.2 3650

398.2 3651

405.1 3652

373.2 3653

408.2 3654

442.2 3655

388.2 3656

333.2 3657

481.3 3658

331.2 3659

3660

331.0 3661

441.2 3662

326.2 3663

492.3 3664

509.3 3665

418.1 3666

208.2 3667

438.2 3668

415.2 3669

356.2 3670

443.2 3671

310.1 3672

297.0 3673

498.3 3674

442.2 3675

461.3 3676

455.3 3677

359.2 3678

476.3 3679

499.3 3680

395.2 3681

493.3 3682

425.2 3683

366.0 3684

378.2 3685

356.2 3686

496.3 3687

379.2 3688

436.2 3689

499.3 3690

415.9 3691

358.0 3692

354.2 3693

343.0 3694

301.2 3695

448.3 3696

496.3 3697

490.3 3698

379.2 3699

3700

3701

375.2 3702

482.3 3703

378.2 3704

342.2 3705

354.4 3706

422.2 3707

252.1 3708

525.3 3709

444.2 3710

356.2 3711

261.0 3712

351.3 3713

3714

401.2 3715

441.2 3716

406.9 3717

457.3 3718

313.1 3719

3720

3721

421.1 3722

478.3 3723

316.2 3724

307.3 3725

461.8 3726

390.2 3727

470.4 3728

371.0 3729

502.3 3730

342.2 3731

372.0 3732

494.3 3733

479.1 3734

362.2 3735

454.3 3736

272.2 3737

399.2 3738

471.4 3739

424.2 3740

369.2 3741

453.1 3742

460.3 3743

445.2 3744

392.2 3745

3746

359.2 3747

442.2 3748

258.1 3749

303.2 3750

444.2 3751

282.3 3752

456.3 3753

413.2 3754

409.0 3755

371.0 3756

476.3 3757

346.0 3758

502.3 3759

480.3 3760

476.3 3761

343.1 3762

414.2 3763

386.2 3764

367.1 3765

362.2 3766

275.0 3767

351.2 3768

536.3 3769

333.2 3770

3771

376.2 3772

436.2 3773

471.3 3774

297.3 3775

385.2 3776

448.3 3777

462.3 3778

273.2 3779

308.2 3780

328.2 3781

381.0 3782

3783

3784

354.1 3785

449.2 3786

445.2 3787

475.3 3788

484.0 3789

343.0 3790

430.2 3791

391.3 3792

355.4 3793

335.9 3794

457.3 3795

3796

470.3 3797

344.2 3798

396.2 3799

439.2 3800

332.2 3801

555.3 3802

264.2 3803

407.2 3804

399.2 3805

404.2 3806

3807

443.2 3808

339.2 3809

3810

421.2 3811

369.2 3812

496.3 3813

3814

384.2 3815

436.2 3816

394.2 3817

354.1 3818

543.3 3819

352.2 3820

402.2 3821

460.3 3822

453.3 3823

470.3 3824

502.3 3825

508.3 3826

337.0 3827

258.1 3828

410.2 3829

367.3 3830

390.1 3831

300.2 3832

351.1 3833

352.2 3834

373.2 3835

3836

384.2 3837

484.3 3838

348.2 3839

388.0 3840

396.2 3841

326.1 3842

302.2 3843

461.3 3844

345.2 3845

448.3 3846

357.1 3847

3848

250.1 3849

445.9 3850

417.2 3851

336.0 3852

254.1 3853

369.1 3854

541.1 3855

420.2 3856

503.1 3857

382.2 3858

340.2 3859

358.1 3860

453.3 3861

362.2 3862

421.1 3863

353.1 3864

384.2 3865

371.2 3866

328.0 3867

249.0 3868

309.2 3869

485.3 3870

431.2 3871

3872

3873

384.2 3874

314.2 3875

459.3 3876

382.2 3877

336.1 3878

260.1 3879

438.2 3880

325.1 3881

296.2 3882

456.3 3883

337.1 3884

376.2 3885

459.3 3886

379.4 3887

446.2 3888

384.2 3889

357.2 3890

459.3 3891

375.2 3892

378.2 3893

354.1 3894

399.2 3895

467.3 3896

351.2 3897

327.3 3898

301.2 3899

348.2 3900

507.3 3901

321.1 3902

451.3 3903

3904

331.1 3905

379.0 3906

331.0 3907

460.3 3908

282.1 3909

3910

594.7 3911

387.2 3912

3913

299.2 3914

423.0 3915

400.1 3916

400.0 3917

351.2 3918

312.2 3919

427.2 3920

297.0 3921

483.3 3922

252.1 3923

308.1 3924

376.2 3925

354.2 3926

3927

442.2 3928

430.2 3929

324.2 3930

399.2 3931

330.2 3932

349.2 3933

314.2 3934

339.0 3935

3936

478.3 3937

430.2 3938

281.0 3939

385.2 3940

490.3 3941

501.3 3942

515.3 3943

483.3 3944

345.3 3945

492.3 3946

481.3 3947

3948

385.2 3949

358.2 3950

507.3 3951

335.2 3952

314.2 3953

415.1 3954

3955

452.3 3956

431.2 3957

321.2 3958

390.2 3959

433.2 3960

325.2 3961

354.2 3962

443.2 3963

408.2

Obs. # Structure Mass 3964

351.2 3965

357.2 3966

397.2 3967

559.3 3968

465.3 3969

455.3 3970

459.3 3971

341.2 3972

504.3 3973

490.1 3974

429.2 3975

459.3 3976

386.2 3977

440.2 3978

409.2 3979

402.2 3980

354.2 3981

490.3 3982

457.3 3983

330.3 3984

419.2 3985

369.2 3986

412.2 3987

447.3 3988

460.3 3989

436.2 3990

461.3 3991

466.1 3992

468.0 3993

359.2 3994

399.2 3995

432.2 3996

293.2 3997

422.2 3998

329.1 3999

389.4 4000

4001

515.3 4002

370.0 4003

463.3 4004

314.3 4005

489.3 4006

399.2 4007

431.4 4008

472.3 4009

4010

427.2 4011

4012

359.9 4013

385.2 4014

372.0 4015

300.2 4016

657.1 4017

345.1 4018

387.2 4019

358.2 4020

401.2 4021

350.2 4022

415.0 4023

392.0 4024

4025

497.3 4026

442.2 4027

286.2 4028

516.3 4029

336.2 4030

396.2 4031

408.2 4032

330.0 4033

383.2 4034

287.0 4035

4036

354.1 4037

493.3 4038

481.3 4039

389.2 4040

501.3 4041

476.3 4042

416.2 4043

344.2 4044

423.8 4045

483.3 4046

452.3 4047

537.7 4048

469.0 4049

501.3 4050

326.0 4051

361.0 4052

495.3 4053

470.3 4054

459.0 4055

393.2 4056

337.2 4057

342.2 4058

422.2 4059

367.2 4060

452.3 4061

357.2 4062

186.2 4063

477.3 4064

351.2 4065

409.2 4066

340.2 4067

408.1 4068

447.0 4069

372.2 4070

405.2 4071

359.2 4072

4073

351.2 4074

311.2 4075

515.3 4076

4077

444.1 4078

417.2 4079

323.2 4080

4081

389.1 4082

539.3 4083

363.0 4084

395.2 4085

408.2 4086

4087

309.2 4088

395.2 4089

455.3 4090

386.2 4091

447.3 4092

463.3 4093

436.2 4094

340.2 4095

505.3 4096

433.2 4097

347.1 4098

376.2 4099

299.1 4100

411.1 4101

426.1 4102

375.1 4103

496.3 4104

352.2 4105

394.2 4106

369.2 4107

311.2 4108

377.2 4109

372.2 4110

341.2 4111

459.3 4112

423.0 4113

351.1 4114

481.3 4115

350.2 4116

420.2 4117

330.1 4118

407.2 4119

426.1 4120

393.2 4121

446.3 4122

338.2 4123

336.2 4124

405.1 4125

408.2 4126

449.3 4127

396.2 4128

461.3 4129

365.2 4130

404.2 4131

470.3 4132

428.2 4133

425.2 4134

382.2 4135

445.2 4136

509.3 4137

426.2 4138

313.1 4139

385.2 4140

483.3 4141

326.1 4142

500.3 4143

427.2 4144

489.3 4145

334.2 4146

359.0 4147

315.3 4148

373.2 4149

462.3 4150

453.3 4151

371.2 4152

410.2 4153

450.3 4154

380.2 4155

407.2 4156

297.1 4157

350.2 4158

390.2 4159

326.0 4160

4161

397.2 4162

340.3 4163

419.2 4164

377.2 4165

397.2 4166

399.2 4167

330.2 4168

392.0 4169

469.3 4170

472.3 4171

416.2 4172

481.3 4173

325.1 4174

4175

528.3 4176

322.1 4177

398.2 4178

374.2 4179

421.2 4180

392.2 4181

409.5 4182

364.2 4183

386.1 4184

339.2 4185

286.2 4186

547.3 4187

359.2 4188

354.2 4189

301.2 4190

436.0 4191

472.3 4192

380.2 4193

315.2 4194

4195

316.2 4196

390.1 4197

393.1 4198

516.3 4199

404.2 4200

452.3 4201

337.8 4202

397.1 4203

350.1 4204

496.3 4205

417.1 4206

458.3 4207

4208

343.0 4209

434.3 4210

357.2 4211

476.3 4212

4213

511.3 4214

342.2 4215

254.1 4216

360.2 4217

344.2 4218

4219

469.3 4220

325.3 4221

322.2 4222

344.2 4223

364.2 4224

285.9 4225

465.3 4226

386.2 4227

427.2 4228

4229

337.2 4230

426.2 4231

343.2 4232

501.3 4233

404.9 4234

210.1 4235

507.3 4236

467.3 4237

336.2 4238

249.1 4239

368.2 4240

426.2 4241

399.2 4242

480.3 4243

360.2 4244

403.2 4245

375.2 4246

340.2 4247

4248

357.0 4249

286.2 4250

341.2 4251

444.2 4252

361.2 4253

432.1 4254

499.3 4255

356.0 4256

310.0 4257

426.2 4258

388.1 4259

428.0 4260

313.9 4261

410.2 4262

443.2 4263

359.0 4264

335.2 4265

411.2 4266

250.0 4267

391.2 4268

490.3 4269

309.2 4270

475.9 4271

449.3 4272

316.0 4273

482.3 4274

497.1 4275

331.2 4276

320.1 4277

509.3 4278

444.2 4279

373.2 4280

541.3 4281

493.3 4282

359.0 4283

300.2 4284

359.2 4285

338.0 4286

446.3 4287

396.2 4288

4289

419.2 4290

444.2 4291

337.3 4292

568.3 4293

375.2 4294

297.0 4295

4296

340.2 4297

4298

482.3 4299

397.2 4300

383.2 4301

382.2 4302

397.1 4303

434.1 4304

359.2 4305

274.2 4306

320.2 4307

308.2 4308

394.2 4309

323.1 4310

356.2 4311

354.2 4312

500.3 4313

4314

384.2 4315

463.3 4316

441.2 4317

346.2 4318

403.2 4319

449.3 4320

476.3 4321

4322

389.2 4323

312.2 4324

439.1 4325

335.2 4326

323.1 4327

380.2 4328

409.2 4329

378.2 4330

340.2 4331

394.2 4332

378.2 4333

434.1 4334

465.3 4335

356.2 4336

443.2 4337

403.2 4338

4339

329.2 4340

423.0 4341

368.2 4342

369.0 4343

326.3 4344

332.0 4345

4346

4347

486.3 4348

433.2 4349

469.3 4350

260.1 4351

393.2 4352

4353

4354

459.3 4355

335.1 4356

351.0 4357

486.3 4358

250.3 4359

379.2 4360

332.2 4361

342.1 4362

4363

562.3 4364

370.2 4365

360.0 4366

402.7

Obs. # Structure Mass 4367

487.1 4368

427.2 4369

421.0 4370

272.2 4371

316.2 4372

4373

409.0 4374

301.9 4375

358.2 4376

326.2 4377

429.2 4378

357.0 4379

363.2 4380

4381

380.2 4382

357.2 4383

4384

369.2 4385

310.0 4386

332.2 4387

375.2 4388

283.3 4389

384.0 4390

302.0 4391

4392

469.3 4393

354.2

Human Cathepsin D FRET Assay

This assay can be run in either continuous or endpoint format. Thesubstrate used below has been described (Y. Yasuda et al., J. Biochem.,125, 1137 (1999)). Substrate and enzyme are commercially available.

The assay is run in a 30 ul final volume using a 384 well Nunc blackplate. 8 concentrations of compound are pre-incubated with enzyme for 30mins at 37 C followed by addition of substrate with continued incubationat 37 C for 45 mins. The rate of increase in fluorescence is linear forover 1 h and is measured at the end of the incubation period using aMolecular Devices FLEX station plate reader. K is are interpolated fromthe IC50s using a Km value of 4 uM and the substrate concentration of2.5 uM.

Reagents

-   Na-Acetate pH 5-   1% Brij-35 from 10% stock (Calbiochem)-   DMSO-   Purified (>95%) human liver Cathepsin D (Athens Research &    Technology Cat# 16-12-030104)-   Peptide substrate (Km=4uM) Mca-Gly-Lys-    Pro-IIe-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH₂ (SEQ ID NO: 1) Bachem    Cat # M-2455-   Pepstatin is used as a contiol inhibitor (Ki˜0.5nM) and is available    from Sigma.-   Nunc 384 well black plates    Final Assay Buffer Conditions-   100 mM Na Acetate pH 5.0-   0.02% Brij-35-   1% DMSO

Compound is diluted to 3× final concentration in assay buffer containing3% DMSO. 10 ul of compound is added to 10 ul of 2.25 nM enzyme (3×)diluted in assay buffer without DMSO, mixed briefly, spun, and incubatedat 37 C for 30 mins. 3× substrate (7.5 uM) is prepared in 1× assaybuffer without DMSO. 10 ul of substrate is added to each well mixed andspun briefly to initiate the reaction. Assay plates are incubated at 37C for 45 mins and read on 384 compatible fluorescence plate reader usinga 328 nm Ex and 393 nm Em.

Compounds of the present invention exhibit hCathD Ki data ranges fromabout 0.1 to about 500 nM, preferably about 0.1 to about 100 nM morepreferably about 0.1 to about 75 nM.

The following are examples of compounds that exhibit hCathD Ki dataunder 75 nM.

structure

The following compound

has a hCath D Ki value of 0.45 nM.

BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) was generated from the full length BACE1 cDNA (full lengthhuman BACE1 cDNA in pCDNA4/mycHisA construct; University of Toronto) byPCR using the advantage-GC cDNA PCR kit (Clontech, Palo Alto, Calif.). AHindIII/PmeI fragment from pCDNA4-sBACE1myc/His was blunt ended usingKlenow and subcloned into the Stu I site of PFASTBACI(A) (Invitrogen). AsBACE1mycHis recombinant bacmid was generated by transposition inDH10Bac cells (GIBCO/BRL). Subsequently, the sBACE1mycHis bacmidconstruct was transfected into sf9 cells using CellFectin (Invitrogen,San Diego, Calif.) in order to generate recombinant baculovirus. Sf9cells were grown in SF 900-II medium (Invitrogen) supplemented with 3%heat inactivated FBS and 0.5× penicillin/streptomycin solution(Invitrogen). Five milliliters of high titer plaque purifiedsBACEmyc/His virus was used to infect 1 L of logarithmically growing sf9cells for 72 hours. Intact cells were pelleted by centrifugation at3000×g for 15 minutes. The supernatant, containing secreted sBACE1, wascollected and diluted 50% v/v with 100 mM HEPES, pH 8.0. The dilutedmedium was loaded onto a Q-sepharose column. The Q-sepharose column waswashed with Buffer A (20 mM HEPES, pH 8.0, 50 mM NaCl).

Proteins, were eluted from the Q-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn were pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn was then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mM NaCl).Bound proteins were then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, CA) were concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity was estimated to be ˜90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatedthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Pentide Hydrolysis Assay.

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin (SEQ ID NO: 1); CIS-Bio International,France), 5 μM unlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; (SEQ ID NO:2) American Peptide Company, Sunnyvale, CA), 7 nM sproBACEl, 20 mM PIPESpH 5.0, 0.1%Brij-35 (protein grade, Calbiochem, San Diego, Calif.), and10% glycerol were preincubated for 30 mm at 30° C. Reactions wereinitiated by addition of substrate in a 5 pA aliquot resulting in atotal volume of 25 μl. After 3 hr at 30° C reactions were terminated byaddition of an equal volume of 2x stop buffer containing 50 mM Tris-HCIpH 8.0, 0.5 M KF, 0.001% Brij-35, 20 μg/ml SAXL665 (cross-linkedallophycocyanin protein coupled to streptavidin; CIS-Blo International,France) (0.5 μg/well). Plates were shaken briefly and spun at 1200xg for10 seconds to pellet all liquid to the bottom of the plate before theincubation. HTRF measurements were made on a Packard Discovery® HTRFplate reader using 337 nm laser light to excite the sample followed by a50 μs delay and simultaneous measurements of both 620 nm and 665 nmemissions for 400 μs.

IC₅₀ determinations for inhibitors, (I), were determined by measuringthe percent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of/and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data was performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top-Bottom)/(1+10^((LogEC50−X)*Hill Slope)); X is thelogarithm of concentration of I, Y is the percent change in ratio and Ystarts at bottom and goes to top with a sigmoid shape.

Compounds of the present invention have an IC₅₀ range from about 0.001to about 500 μM, preferably about 0.001 to about 100 μM, more preferablyabout 0.001 to about 20 μM.

Examples of compounds with human BACE 1 IC50<1 μM are listed below:

The following compounds below were named with the CAS name generatingprogram: ACD/Labs Version 6.0; (Advanced Chemistry Development, Inc./110Yonge Street/14th floor/Toronto, Ontario, Canada M5C 1T4). Examples ofcompounds with a BACE-1Ki less than 5 micromolar (uM) are listed below:

-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(2,2,2-trifluoroethyl)--   3-[5-[5-[(E)-3-(4-FLUOROPHENYL)-2-PROPENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   3′-(4(R)-CYCLOPROPYL-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL)-4-FLUORO[1,1′-BIPHENYL]-3-CARBONITRILE-   3-CYANO-N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZENESULFONAMIDE    (RACEMIC)-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]CYCLOPROPANEACETAMIDE    (RACEMIC)-   5-[4-(3-CHLOROPHENYL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE-   PIPERIDINE,    1-(3-AMINO-1-OXOPROPYL)-4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]--   2-IMINO-5-METHYL-5-[3-(3-PYRIDINYL)PHENYL]-3-[[3-(TETRAHYDRO-1,1-DIOXIDO-2H-1,2-THIAZIN-2-YL)PHENYL]METHYL]-4-IMIDAZOLIDINONE    (RACEMIC)-   5(R)-[3-(5-CHLORO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]METHANESULFONAMIDE-   5-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]BENZO[b]THIEN-3-YL]-2-THIOPHENECARBONITRILE-   2-IMINO-5-[3-(5-METHOXY-3-PYRIDINYL)PHENYL]-5-METHYL-3-[[5-OXO-1-(PHENYLMETHYL)-3-PYRROLIDINYL]METHYL]-4-IMIDAZOLIDINONE-   urea,    N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-N′-(4-chlorophenyl)--   5-(3-BROMOPHENYL)-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE-   5(R)-ETHYLTETRAHYDRO-2-IMINO-6(S)-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3-[2-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-THIAZOLYL]BENZONITRILE-   2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(1-METHYL-1H-INDOL-5-YL)-4(1H)-PYRIMIDINONE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(2-METHYL-2H-INDAZOL-5-YL)-4(1H)-PYRIMIDINONE    (ISOMER 2)-   1-piperidinecarboxamide,    N-(3-fluorophenyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]--   3-[5-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)-3-THIENYL]BENZONITRILE-   3-[2-ETHYL-5-(5(R)-ETHYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(METHYLSULFONYL)PYRROLIDINE-   1-[3-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)PHENYL]-3-PYRROLIDINECARBONITRILE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[3-(1-PIPERIDINYL)PHENYL]-4(1H)-PYRIMIDINONE-   5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(R)-[(2-OXO-3(S)-PYRROLIDINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   5(R)-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   6(S)-[3-(5-BENZOTHIAZOLYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-IMINO-5-OXO-4,4-DIPHENYL-N,N-DIPROPYL-1-IMIDAZOLIDINEPENTANAMIDE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-METHYL-5-[3-(TRIFLUOROMETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE-   6(S)-[7-(6-FLUORO-3-PYRIDINYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5-[′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(1-METHYL-1H-IMIDAZOL-2-YL)-4-IMIDAZOLIDINONE-   6(S)-[7-(3-FLUOROPHENYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(2-naphthalenylsulfonyl)--   piperidine,    1-(ethylsulfonyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]--   5(R)-[3-(4-BROMO-2-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-METHYLBENZONITRILE-   5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]-1,3-BENZENEDICARBONITRILE-   6(S)-[4-BROMO-5-(5-BROMO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-FLUORO-5-[4-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE-   6(S)-(2,4-DIFLUOROPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5-[3-[(1-ETHYL-1H-PYRAZOL-5-YL)AMINO]PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE-   1-ACETYL-4-[[2-IMINO-4-[5′-METHOXY-2′-[(PHENYLAMINO)METHYL][1,1′-BIPHENYL]-3-YL]-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(4-PYRIDINYL)BENZO[b]THIEN-5-YL]-4(1H)-PYRIMIDINONE-   PIPERIDINE,    3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(1-OXOBUTYL)-,    (3S)--   6(S)-[3-(2-CYCLOPROPYLETHYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   PIPERIDINE,    1-ACETYL-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-,    (3S)--   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDAZINECARBOXAMIDE-   2-IMINO-3-METHYL-5-PHENYL-5-[4-(3-PYRIDINYL)-2-THIENYL]-4-IMIDAZOLIDINONE-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]-2-THIOPHENESULFONAMIDE    (RACEMIC)-   6(S)-[3-(3-BROMOPHENYL)-1-METHYL-1H-PYRAZOL-5-YL]TETRAHYDRO-2-IMINO-3,5,5,6-TETRAMETHYL-4(1H)-PYRIMIDINONE-   6(S)-(1,3-DIMETHYL-1H-THIENO[2,3-c]PYRAZOL-5-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   6(S)-[4-(3-CHLOROPHENYL)-2-PYRIDINYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-IMINO-3-[(1-METHYL-1H-PYRAZOL-5-YL)METHYL]-5,5-DIPHENYL-4-IMIDAZOLIDINONE-   6(S)-[4-(3-ETHOXY-5-FLUOROPHENYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-5-METHOXY-1,4-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE    (ENANTIOMER C)-   5(R)-[[3(R)-(CYCLOHEXYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE-   2-IMINO-3-METHYL-5-PHENYL-5-[4-(5-PYRIMIDINYL)-2-THIENYL]-4-IMIDAZOLIDINONE-   6(S)-[3-(3-BROMOPHENYL)-5-ISOTHIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(3-PYRIDINYL)-2-THIAZOLYL]-4(1H)-PYRIMIDINONE-   4-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]BENZOYL]MORPHOLINE-   5-[5-FLUORO-3′-METHOXY[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE    (RACEMIC)-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(TRIFLUOROMETHOXY)PHENYL]-2-PYRIDINYL]-4(1H)-PYRIMIDINONE-   1-ACETYL-4-[[4-(3′-HYDROXY[1,1′-BIPHENYL]-3-YL)-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(PHENYLSULFONYL)PYRROLIDINE-   2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3(S)-(3-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-1,3-BENZENEDICARBONITRILE-   CYCLOPENTANECARBOXAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(methylsulfonyl)--   3-CHLORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]-3-FURANCARBOXAMIDE    (RACEMIC)-   3-[4-(4-CYCLOPROPYL-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL)-2-THIENYL]BENZONITRILE-   6-(5-BROMO-2-THIENYL)-6-CYCLOPROPYLTETRAHYDRO-2-IMINO-3-METHYL-4(1H)-PYRIMIDINONE-   5-[5-[5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-FLUORO-3-THIENYL]-2-FLUOROBENZONITRILE-   3-FLUORO-5-[2-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-5-THIAZOLYL]BENZONITRILE-   2-IMINO-5,5-DIPHENYL-3-(3-PYRIDINYLMETHYL)-4-IMIDAZOLIDINONE-   3-[[4-(3-BROMOPHENYL)-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-N,N-DIPROPYLBENZAMIDE    (RACEMIC)-   1-[[5-[[4-(3-BROMOPHENYL)-4-CYCLOPROPYL-2-IMINO-5-OXO-1-IMIDAZOLIDINYL]METHYL]-3-PYRIDINYL]CARBONYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]BENZENESULFONAMIDE-   5-[4-FLUORO-3-(3-PYRIDINYL)PHENYL]-2-IMINO-3,5-DIMETHYL-A-IMIDAZOLIDINONE    (RACEMIC)-   5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(R)-[(2-PHENYLETHYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-(S)-CYCLOHEXYL]-N′-PHENYLUREA-   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-[[4-(trifluoromethoxy)phenyl]sulfonyl]--   4-FLUORO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIOPHENECARBONITRILE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-METHYL-2-THIENYL]BENZONITRILE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[1-(4-METHYLPHENYL)-4-PIPERIDINYL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5(S)-CYCLOPROPYL-2-IMINO-3-METHYL-5-[[3(R)-(2-QUINOLINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   N-ETHYL-N-[2-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]ETHYL]ACETAMIDE    (RACEMIC)-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-METHYL-3-THIENYL]BENZONITRILE-   1-BUTANESULFONAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(3-PYRIDINYL)-2-THIENYL]-4(1H)-PYRIMIDINONE-   PIPERIDINE,    1-(CYCLOPROPYLSULFONYL)-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-,    (3R)--   3-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-2-METHYL-3-THIENYL]-5-METHOXYBENZONITRILE-   6(S)-(3-BROMO-1H-INDAZOL-6-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5-[4-(5-CHLORO-3-PYRIDINYL)-2-THIENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[1-(hydroxymethyl)propyl]-2-imino--   N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDINECARBOXAMIDE-   2-IMINO-3,5-DIMETHYL-5-[3-(5-METHYL-3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE    (RACEMIC)-   6(S)-(2,4-DIFLUOROPHENYL)-5(R)-[1-(4-FLUOROPHENYL)-4-PIPERIDINYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-propanesulfonamide,    N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]--   2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3(R)-(3-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   benzeneacetamide,    N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]--   4(S)-[4-(3-CYANOPHENYL)-2-THIENYL]HEXAHYDRO-2-IMINO-1,4-DIMETHYL-6-OXO-5(R/S)-PYRIMIDINEACETONITRILE-   PIPERIDINE,    1-(CYCLOPROPYLCARBONYL)-3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-,    (3S)--   2-IMINO-5-[3-(5-METHOXY-3-PYRIDINYL)PHENYL]-5-METHYL-3-[(5-OXO-1-PHENYL-3-PYRROLIDINYL)METHYL]-4-IMIDAZOLIDINONE-   3(R)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-N-PHENYL-1-PYRROLIDINECARBOXAMIDE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   3-[5-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)-3-THIENYL]BENZONITRILE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(1-methylethyl)--   5(R)-CYCLOPROPYL-6(S)-[4-(2-FLUORO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   6(S)-[1-(3-ETHYLPHENYL)-1H-PYRAZOL-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-IMINO-5-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-5-METHYL-3-[[3-(TETRAHYDRO-1,1-DIOXIDO-2H-1,2-THIAZIN-2-YL)PHENYL]METHYL]-4-IMIDAZOLIDINONE    (RACEMIC)-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-3-cyclopentyl-5-cyclopropyl-2-imino--   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(METHYLTHIO)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE-   1-ACETYL-4-[[4-[2′-FORMYL-5′-METHOXY[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-N-METHYLMETHANESULFONAMIDE-   5-[3-(3-CHLOROPYRAZINYL)PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE    (RACEMIC)-   CYCLOHEXANECARBOXAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   2,6-DICHLORO-N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-4-PYRIDINECARBOXAMIDE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1    (R)CYCLOHEXYL]-2-PYRIDINECARBOXAMIDE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-[3-(1-METHYLETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE-   urea,    N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-N′-phenyl--   6(S)-(7-BROMOBENZO[b]THIEN-2-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3-[5-(1-ETHYLHEXAHYDRO-2-IMINO-4(S)-METHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   1-[3-[(2-IMINO-4-METHYL-5-OXO-4-PHENYL-1-IMIDAZOLIDINYL)METHYL]BENZOYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE-   6(S)-(BENZO[b]THIEN-2-YL)TETRAHYDRO-2-IMINO-3,5(R),6-TRIMETHYL-4(1H)-PYRIMIDINONE-   5-CYCLOPROPYL-5-[4-[3-(HYDROXYMETHYL)PHENYL]-2-THIENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   5-CYCLOPROPYL-5-[3-(1H-IMIDAZOL-1-YL)PHENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(1H-PYRAZOL-1-YL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE    (ISOMER 2)-   2-FLUORO-5-[5-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)-3-THIENYL]BENZONITRILE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[(E)-3-PHENYL-2-PROPENYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-3-PYRIDINECARBOXAMIDE-   5(R)-CYCLOPROPYL-5-(4′-HYDROXY-3′-METHOXY[,    1′-BIPHENYL]-3-YL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   3-[5-(4(S)-ETHYLHEXAHYDRO-2-IMINO-1-METHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE-   2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(PYRAZINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   5-[2-(3,5-DICHLOROPHENYL)-4-PYRIDINYL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-5-CYCLOHEXYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]CYCLOPENTANECARBOXAMIDE-   5-[4-(1,3-BENZODIOXOL-5-YL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-4-HYDROXYBENZONITRILE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(3-THIENYL)BENZO[b]THIEN-3-YL]-4(1H)-PYRIMIDINONE-   PIPERIDINE,    4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(3-PYRIDINYLACETYL)--   N-[[[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]AMINO]CARBONYL]BENZAMIDE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-2-NAPHTHALENEACETAMIDE-   5-[5-(3,4-DICHLOROPHENYL)HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-THIOPHENECARBONITRILE-   N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]ETHANESULFONAMIDE-   N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-1-PROPANESULFONAMIDE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE-   6(S)-ETHYLTETRAHYDRO-2-IMINO-3-METHYL-6-[4-(3-PYRIDINYL)-2-THIENYL]-4(H)-PYRIMIDINONE-   6(S)-[3-(2-FLUORO-3-PYRIDINYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   4-CHLORO-3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)BENZO[b]THIEN-7-YL]BENZONITRILE-   1-piperidinecarboxamide,    N-(3-chlorophenyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]--   3′-(TETRAHYDRO-3-IMINO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-5-YL)[1,1′-BIPHENYL]-3-CARBONITRILE-   6(S)-[5-(3-ETHYLPHENYL)-1-METHYL-1H-PYRAZOL-3-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   PIPERIDINE,    3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(1-OXOBUTYL)-,    (3R)--   1-ACETYL-4-[[2-IMINO-4-[3-(1H-INDOL-4-YL)PHENYL]-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   1-ACETYL-4-[[4(R)-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-4-CYCLOPROPYL-2-IMINO-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   5-(3-BROMOPHENYL)-5-CYCLOHEXYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   6(S)-[5-(3-BROMOPHENYL)-2-THIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5(R)-[4-(1,1-DIFLUOROETHYL)PHENYL]TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(2,4,6-TRIFLUOROPHENYL)-4(1H)-PYRIMIDINONE-   piperidine,    1-[(3-chloro-4-fluorophenyl)sulfonyl]-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]--   5-[4-CHLORO-5-(HEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-METHYL-2-THIENYL]-2-FLUOROBENZONITRILE-   6(S)-[4-(6-CHLOROPYRAZINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-5-METHOXYBENZONITRILE-   3-CHLORO-5-[5-(5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]BENZONITRILE-   3-[2-(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)ETHYL]-1-(METHYLSULFONYL)PIPERIDINE    (RACEMIC)-   3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(CYCLOHEXYLCARBONYL)PYRROLIDINE-   1-ACETYL-4-[[2-IMINO-4-METHYL-4-[3-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   2-THIOPHENEACETAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(S)-(3(S)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   PIPERIDINE,    3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-(PROPYLSULFONYL)-,    (3R)--   3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(CYCLOHEXYLACETYL)PYRROLIDINE-   5-[3′,5′-DICHLORO[1,1′-BIPHENYL]-3-YL]-DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE-   6(S)-[1-(CYCLOPENTYLMETHYL)-1H-INDAZOL-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   1-BENZOYL-3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PYRROLIDINE-   CYCLOPROPANESULFONAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   5-(3-BROMOPHENYL)-5-CYCLOBUTYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3-(2-METHYL-4-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE-   2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(2-QUINOXALINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZAMIDE    (RACEMIC)-   BUTANAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-3,3-DIMETHYL--   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[1-METHYL-3-(2-THIENYL)-1H-INDOL-5-YL]-4(1H)-PYRIMIDINONE-   3-[3-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)BENZO[b]THIEN-7-YL]BENZONITRILE-   3-[5-[(1R)-1′,2,3,3′,4′,6′-HEXAHYDRO-2′-IMINO-5-METHOXY-1′,4′(S)-DIMETHYL-6′-OXOSPIRO[1H-INDENE-1,5′(2′H)-PYRIMIDIN]-4′-YL]-3-THIENYL]BENZONITRILE-   BENZAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   TETRAHYDRO-2-IMINO-6(S)-[5-(3-METHOXYPHENYL)-4-METHYL-2-THIENYL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5(R)-[3-(5-CHLORO-2-FLUORO-3-PYRIDINYL)PHENYL]-5-CYCLOPROPYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-3-PYRIDINECARBOXAMIDE-   5-[3′-(HYDROXYMETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE-   5-[3-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)PHENYL]-3-PYRIDINECARBONITRILE    (RACEMIC)-   6(S)-[5-CHLORO[2,3′-BITHIOPHEN]-5′-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE-   1-ACETYL-4-[[4-[3-(3-FURANYL)PHENYL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   6(S)-(2,6-DIFLUOROPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-5(R)-[4-(TRIFLUOROMETHYL)PHENYL]-4(1H)-PYRIMIDINONE-   5-[5(R)-(4-CYCLOPROPYLPHENYL)HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIOPHENECARBONITRILE-   5-(3-BROMOPHENYL)-2-IMINO-3-METHYL-5-(1-METHYLETHYL)-4-IMIDAZOLIDINONE-   6(S)-[4-[3-CHLORO-5-(1-METHYLETHOXY)PHENYL]-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[2-(1-PIPERIDINYL)ETHYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5-[5-(5(S)-CYCLOBUTYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-3-PYRIDINECARBONITRILE-   5-[5-(5-BROMOHEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-FLUOROBENZONITRILE-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]METHANESULFONAMIDE    (RACEMIC)-   2-IMINO-3-[(4-METHYLPHENYL)METHYL]-5,5-DIPHENYL-4-IMIDAZOLIDINONE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5(R)-PROPYL-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   5(R)-CYCLOPROPYLTETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[5-[3-(TRIFLUOROMETHYL)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE-   2-IMINO-5,5-DIPHENYL-3-[(TETRAHYDRO-2H-PYRAN-4-YL)METHYL]-4-IMIDAZOLIDINONE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIAZOLYL]BENZONITRILE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-2-QUINOLINECARBOXAMIDE-   N-[3(S)-[[2-IMINO-1-METHYL-5-OXO-4(R)-(2-PHENYLETHYL)-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]ACETAMIDE-   N-ETHYL-N-[2-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]ETHYL]METHANESULFONAMIDE    (RACEMIC)-   2-IMINO-3-METHYL-5-PHENYL-5-[3-(2-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE    (RACEMIC)-   6(S)-(3-CHLORO-2-THIENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3′-(HEXAHYDRO-2-IMINO-1,4(R)-DIMETHYL-5-METHYLENE-6-OXO-4-PYRIMIDINYL)[1,1′-BIPHENYL]-3-CARBONITRILE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(1-methylpropyl)--   2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-4-METHYL-3-THIENYL]BENZONITRILE-   2-IMINO-3-METHYL-5(R)-(2-PHENYLETHYL)-5-[[3-(2-PYRIDINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   6(S)-[5-(3-CHLOROPHENYL)-2-THIAZOLYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(2-THIAZOLYL)-4-IMIDAZOLIDINONE-   2-IMINO-3-METHYL-5-PHENYL-5-[3-[(PHENYLMETHYL)AMINO]PHENYL]-4-IMIDAZOLIDINONE    (RACEMIC)-   6(S)-[7-(2-CHLORO-5-METHOXYPHENYL)BENZO[b]THIEN-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5(R)-CYCLOPROPYL-5-[3-(2-FLUORO-3-PYRIDINYL)PHENYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   6(S)-(3-BROMO-1-METHYL-1H-INDOL-5-YL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   benzenesulfonamide,    N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]--   2-IMINO-3,5(R)-DIMETHYL-5-[[3(R)-(2-QUINOLINYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   1-ACETYL-4-[[4-[3-[(1-ETHYL-1H-PYRAZOL-5-YL)AMINO]PHENYL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE    (RACEMIC)-   6(S)-[2-(CYCLOHEXYLMETHYL)-2H-INDAZOL-5-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   6(S)-(BENZO[b]THIEN-5-YL)TETRAHYDRO-2-IMINO-3-(2-METHOXYETHYL)-6-METHYL-4(1H)-PYRIMIDINONE-   5(S)-[[3(R)-[(8-CHLORO-2-QUINOLINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-5-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   6(S)-BENZO[b]THIEN-5-YLTETRAHYDRO-3-(2-HYDROXYETHYL)-2-IMINO-6-METHYL-4(1H)-PYRIMIDINONE-   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(phenylsulfonyl)--   5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(R)-(3(R)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   3-BROMO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   3-[2-BROMO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   6(S)-(2,4-DIFLUOROPHENYL)-5(R)-[4-(1,1-DIOXIDO-2-ISOTHIAZOLIDINYL)PHENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-IMINO-3-METHYL-5(R)-[[3(R)-(PHENYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE-   1-ACETYL-4-[[2-IMINO-4-METHYL-5-OXO-4-[3-(1H-PYRAZOL-4-YL)PHENYL]-1-IMIDAZOLIDINYL]METHYL]PIPERIDINE-   TETRAHYDRO-2-IMINO-3,6-DIMETHYL-6(S)-[3-(1-PYRROLIDINYL)PHENYL]-4(1H)-PYRIMIDINONE-   CYCLOPENTANEACETAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   2-IMINO-5,5-DIPHENYL-3-(3-THIENYLMETHYL)-4-IMIDAZOLIDINONE-   DIHYDRO-5-[3′-METHOXY[1,1′-BIPHENYL]-3-YL]-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE-   5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(S)-[(2-PHENYLETHYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   5-[5-(5(S)-CYCLOBUTYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-2-FLUOROBENZONITRILE-   benzamide,    N-[[5-chloro-3′-(2-imino-1,4-dimethyl-5-oxo-4-imidazolidinyl)[1,1′-biphenyl]-2-yl]methyl]-2-methoxy--   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-3-cyclobutyl-5-cyclopropyl-2-imino--   3-CHLORO-5-[5-(5(S)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(3-PHENYLPROPYL)-5-(1H-PYRAZOL-1-YL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]METHYL]-1(R)-CYCLOHEXYL]-2-METHOXYBENZAMIDE-   5-[3-(5-BROMO-3-PYRIDINYL)PHENYL]-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE-   5(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-5-[[3(S)-[(2-OXO-3(S)-PYRROLIDINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-4-IMIDAZOLIDINONE-   3-[5-[5-[(E)-3-(3-FLUOROPHENYL)-2-PROPENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5-[3-BROMO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]-3-PYRIDINECARBONITRILE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[7-(3-PYRIDINYL)BENZO[b]THIEN-5-YL]-4(1H)-PYRIMIDINONE-   5-[5′-CHLORO-2′-(2-HYDROXYETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE-   5-[5′-CHLORO-2′-[2-(FORMYLOXY)ETHYL][1,1′-BIPHENYL]-3-YL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE-   BUTANAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]-3-METHYL--   5-CYCLOPROPYL-2-IMINO-5-[4-(5-METHOXY-3-PYRIDINYL)-2-THIENYL]-3-METHYL-4-IMIDAZOLIDINONE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(2-PYRIMIDINYL)-4-IMIDAZOLIDINONE-   ethanesulfonamide,    N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]--   5-[3′-BROMO-5′-(TRIFLUOROMETHOXY)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE    (RACEMIC)-   N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-4-PYRIDAZINECARBOXAMIDE-   6(S)-(4-ETHYL-2-THIENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   4-CHLORO-5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIOPHENECARBONITRILE-   5-[5-(4-CYCLOPROPYLHEXAHYDRO-2-IMINO-1-METHYL-6-OXO-4-PYRIMIDINYL)-2-THIENYL]-2-FLUOROBENZONITRILE-   TETRAHYDRO-2-IMINO-6(S)-[1-(3-IODOPHENYL)-1H-PYRAZOL-4-YL]-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3′-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5(R)-PROPYL-4-PYRIMIDINYL)[1,1′-BIPHENYL]-3-CARBONITRILE-   5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]-1,3-BENZENEDICARBONITRILE-   1-[3-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]BENZOYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE-   TETRAHYDRO-2-IMINO-5(R)-(4-METHOXYPHENYL)-3,6(S)-DIMETHYL-6-(5-THIAZOLYL)-4(1H)-PYRIMIDINONE-   1-[[5-[(4-CYCLOPROPYL-2-IMINO-5-OXO-4-PHENYL-1-IMIDAZOLIDINYL)METHYL]-3-PYRIDINYL]CARBONYL]-2(R)-(METHOXYMETHYL)PYRROLIDINE-   5-(3-BROMOPHENYL)-5-CYCLOPENTYL-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[3-(diethylamino)propyl]-2-imino--   5(R)-(4-CYCLOPROPYLPHENYL)-6(S)-[2′-FLUORO[2,3′-BIPYRIDIN]-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3-(6-METHYL-2-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE-   N-[3(S)-[[4(R)-(2-CYCLOHEXYLETHYL)-2-IMINO-1-METHYL-5-OXO-4-IMIDAZOLIDINYL]ETHYL]-1(R)-CYCLOHEXYL][1,1′-BIPHENYL]-2-CARBOXAMIDE-   3-[5-[HEXAHYDRO-2-IMINO-4(S)-METHYL-6-OXO-1-(4-PYRIDINYLMETHYL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5(R)-CYCLOPROPYL-5-[3′-(HYDROXYMETHYL)[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   TETRAHYDRO-2-IMINO-6(S)-(3-IODOPHENYL)-3,6-DIMETHYL-5(R)-PROPYL-4(1H)-PYRIMIDINONE-   2-IMINO-5-PHENYL-3-(4-PIPERIDINYLMETHYL)-5-[3-(3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE-   5-[5-[5(R)-CYCLOPROPYLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]-2-FLUOROBENZONITRILE-   5(R)-[[3(R)-(CYCLOPENTYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-5-(2-PHENYLETHYL)-4-IMIDAZOLIDINONE-   6(S)-[4-(2,6-DIFLUORO-3-PYRIDINYL)-2-THIENYL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(S)-(3(R)-HYDROXY-1-PYRROLIDINYL)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(1-PROPYL-1H-INDAZOL-6-YL)-4(1H)-PYRIMIDINONE-   6(S)-(4-FLUORO-2-METHYLPHENYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-(7-PHENYLBENZO[b]THIEN-3-YL)-4(1H)-PYRIMIDINONE-   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-(propylsulfonyl)--   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-5-(CYCLOPROPYLMETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   piperidine,    4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]-1-[(4-methoxyphenyl)sulfonyl]--   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[4-(5-PYRIMIDINYL)-2-THIENYL]-4(1H)-PYRIMIDINONE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-2-imino--   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-[3-(4-PYRIDINYL)PROPYL]-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-3-METHYL-5-(1-METHYLCYCLOPROPYL)-4-IMIDAZOLIDINONE-   5-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-5-METHYL-3-[(1-METHYL-3(S)-PYRROLIDINYL)METHYL]-4-IMIDAZOLIDINONE-   6(S)-(4-BROMO-2-FURANYL)TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   3(S)-[[4-[3′-CHLORO[1,1′-BIPHENYL]-3-YL]-2-IMINO-4-METHYL-5-OXO-1-IMIDAZOLIDINYL]METHYL]-1-(PHENYLACETYL)PYRROLIDINE-   3-(3-FURANYLMETHYL)-2-IMINO-5,5-DIPHENYL-4-IMIDAZOLIDINONE-   5(R)-(2-CYCLOHEXYLETHYL)-5-[[3(R)-(DIMETHYLAMINO)-1(S)-CYCLOHEXYL]METHYL]-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-5(R)-[3-(1-METHYLETHOXY)PHENYL]-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   PIPERIDINE,    □4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-1-[(1-PHENYLCYCLOPROPYL)CARBONYL]--   BUTANAMIDE,    N-[3-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]PHENYL]--   3-[5-[HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-5-(3-PHENYLPROPYL)-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]-N,N-DIPROPYL-1H-IMIDAZOLE-2-CARBOXAMIDE-   N-[[5-CHLORO-3′-(2-IMINO-1,4-DIMETHYL-5-OXO-4-IMIDAZOLIDINYL)[1,1′-BIPHENYL]-2-YL]METHYL]-4-PYRIDINECARBOXAMIDE-   6(S)-[2′-FLUORO[2,3′-BIPYRIDIN]-4-YL]TETRAHYDRO-2-IMINO-3,6-DIMETHYL-4(1H)-PYRIMIDINONE-   2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-1-METHYL-1H-PYRAZOL-3-YL]BENZONITRILE-   3-CHLORO-5-[5-(HEXAHYDRO-2-IMINO-1,4(S),5(R)-TRIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE-   N-[3-(2-IMINO-1-METHYL-5-OXO-4-PHENYL-4-IMIDAZOLIDINYL)PHENYL]BENZENESULFONAMIDE    (RACEMIC)-   2-FLUORO-5-[(4S)-2′,3′,5′,6,6′,7-HEXAHYDRO-2′-IMINO-1′-METHYL-6′-OXOSPIRO[BENZO[b]THIOPHENE-4(5H),    4′(1′H)-PYRIMIDIN]-2-YL]BENZONITRILE-   5-[3-(5-FLUORO-3-PYRIDINYL)PHENYL]-2-IMINO-3,5-DIMETHYL-4-IMIDAZOLIDINONE-   5-[2′-FLUORO-5′-METHOXY[1,1′-BIPHENYL]-3-YL]-DIHYDRO-2,5-DIMETHYL-2H-1,2,4-OXADIAZIN-3(4H)-IMINE-   5-[3-(3-FURANYL)PHENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE    (RACEMIC)-   piperidine,    1-(butylsulfonyl)-4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]--   2-IMINO-3-METHYL-5-PHENYL-5-[3-(3-PYRIDINYL)PHENYL]-4-IMIDAZOLIDINONE    (ENANTIOMER B)-   5(S)-[[3(R)-[(6-CHLORO-2-QUINOXALINYL)AMINO]-1(S)-CYCLOHEXYL]METHYL]-5-(2-CYCLOHEXYLETHYL)-2-IMINO-3-METHYL-4-IMIDAZOLIDINONE-   3-[5-[5(R)-BENZO[b]THIEN-3-YLHEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-3-THIENYL]BENZONITRILE-   5-[5(R)-[3-(1,1-DIFLUOROETHYL)PHENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-1H-IMIDAZOLE-   5-CYCLOPROPYL-2-IMINO-3-METHYL-5-[4-METHYL[2,3′-BITHIOPHEN]-5′-YL]-4-IMIDAZOLIDINONE-   1-butanesulfonamide,    N-[4-[(2-imino-5-oxo-4,4-diphenyl-1-imidazolidinyl)methyl]phenyl]--   5-[4-(3-FLUOROPHENYL)-2-THIENYL]-2-IMINO-3-METHYL-5-PHENYL-4-IMIDAZOLIDINONE-   2-IMINO-5,5-DIPHENYL-3-[[1-(2-QUINOLINYL)-4-PIPERIDINYL]METHYL]-4-IMIDAZOLIDINONE-   PIPERIDINE,    1-(AMINOACETYL)-4-[(2-IMINO-5-OXO-4,4-DIPHENYL-1-IMIDAZOLIDINYL)METHYL]--   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-2-imino-3-(tetrahydro-2H-pyran-4-yl)--   3′-[1-[(1-ACETYL-4-PIPERIDINYL)METHYL]-2-IMINO-4-METHYL-5-OXO-4-IMIDAZOLIDINYL]-N-(2-FURANYLMETHYL)[1,1′-BIPHENYL]-3-CARBOXAMIDE-   5(R)-CYCLOPROPYL-2-IMINO-3-METHYL-5-[3′-(METHYLTHIO)[1,1′-BIPHENYL]-3-YL]-4-IMIDAZOLIDINONE-   4-imidazolidinone,    5-(3′-chloro[1,1′-biphenyl]-3-yl)-5-cyclopropyl-3-[2-hydroxy-1-(hydroxymethyl)ethyl]-2-imino--   2-FLUORO-5-[5-(HEXAHYDRO-2-IMINO-5-METHOXY-1,4-DIMETHYL-6-OXO-4-PYRIMIDINYL)-3-THIENYL]BENZONITRILE    (ENANTIOMER B)-   5-[5(R)-[4-(1,1-DIFLUOROETHYL)PHENYL]HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL]-2-THIOPHENECARBONITRILE-   4-[4(S)-[4-(3-CYANOPHENYL)-2-THIENYL]HEXAHYDRO-2-IMINO-1,4-DIMETHYL-6-OXO-5(R)-PYRIMIDINYL]-N,N-DIMETHYL-1-PIPERIDINECARBOXAMIDE-   TETRAHYDRO-2-IMINO-3,6(S)-DIMETHYL-6-[3-METHYL-4-[3-(TRIFLUOROMETHOXY)PHENYL]-2-THIENYL]-4(1H)-PYRIMIDINONE-   3-[5-(HEXAHYDRO-2-IMINO-1,4(S)-DIMETHYL-6-OXO-4-PYRIMIDINYL)-2-(1,2,3,6-TETRAHYDRO-1-PHENYL-4-PYRIDINYL)-3-THIENYL]BENZONITRILE    Human Mature Renin Enzyme Assay:

Human Renin was cloned from a human kidney cDNA library and C-terminallyepitope-tagged with the V5-6His sequence into pCDNA3.1.pCNDA3.1-Renin-V5-6His was stably expressed in HEK293 cells and purifiedto >80% using standard Ni-Affinity chromatography. The prodomain of therecombinant human renin-V5-6His was removed by limited proteolysis usingimmobilized TPCK-trypsin to give mature-human renin. Renin enzymaticactivity was monitored using a commercially available fluorescenceresonance energy transfer (FRET) peptide substrate, RS-1 (MolecularProbes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.1%Brij-35 and 5% DMSO buffer for 40 mins at 30 degrees celsius in thepresence or absence of different concentrations of test compounds.Mature human Renin was present at approximately 200 nM. Inhibitoryactivity was defined as the percent decrease in renin inducedfluorescence at the end of the 40 min incubation compared to vehiclecontrols and samples lacking enzyme.

Compound I% of hRenin at 100 μM

68.8

75.3

76.9

In another embodiment of a compound of formula I having the structuralformula

or a stereoisomer, tautomer, or pharmaceutically acceptable salt,solvate or ester thereof, wherein

W is —C(═O)—;

X is —N(R⁵)—;

U is a bond;

R¹, R² and R⁵ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R³ and R⁴ are independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR²⁰, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, andheteroarylalkyl groups in R¹, R², R³, R⁴, and R⁵ are independentlyunsubstituted or substituted by 1 to 5 R²¹ groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁵), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷)—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴,C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl,R²⁷-arylalkyl, R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl;

provided that when R¹ is methyl, X is —N(R⁵)—, R² is H, W is —C(O)— andU is a bond, (R³, R⁴) is not (H, H), (benzyl, H) or (i-butyl, H).

In another embodiment of a compound of formula I having the structuralformula

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor ester thereof, wherein

W is —C(═O)—;

X is —N(R⁵)—;

U is a bond;

R¹, R² and R⁵ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R³ is independently selected from the group consisting of aryl andheteroaryl;

R⁴ is independently selected from the group consisting of H, aryl,heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR²⁰, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,aryl and heteroaryl groups in R¹, R², R³, R⁴ and R⁵ are independentlyunsubstituted or substituted by 1 to 5 R²¹ groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴,C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl, R²-arylalkyl,R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl;

provided that when R¹ is methyl, X is —N(R⁵)—, R² is H, W is —C(O)— andU is a bond, (R³, R⁴) is not (phenyl, phenyl), (H, phenyl), (benzyl,phenyl), (i-butyl, phenyl), (OH-phenyl, phenyl), (halo-phenyl, phenyl),or (CH₃O-phenyl, NO₂-phenyl);

provided that when X is —N(R⁵)—, R¹ and R⁵ are each H, W is —C(O)— and Uis a bond, (R³, R⁴) is not (optionally substituted phenyl, optionallysubstituted benzyl), (optionally substituted phenyl, heteroarylalkyl) or(heteroaryl, heteroarylalkyl).

In another embodiment of a compound of formula I having the structuralformula

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor ester thereof, wherein

W is —C(═O)—;

X is —N(R⁵)—;

U is a —(C(R⁶)(R⁷))—;

R¹, R² and R⁵ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R³ and R⁴ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, —SH, —SR¹⁹, —CN,—OR⁹, —N(R¹¹)(R¹²) and halo;

R⁶ and R⁷ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl and arylalkyl;

R⁸ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R⁹ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R¹⁰ is independently selected from the group consisting of H, alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and—N(R¹⁵)(R¹⁶);

R¹¹ and R¹² are independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,—C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰, —C(O)N(R¹⁵)(R¹⁶),—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, andheteroarylalkyl groups in R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ areindependently unsubstituted or substituted by 1 to 5 R²¹ groupsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵,—S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶,—P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵;—CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(R¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴,C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl,R²⁷-arylalkyl, R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl.

In another embodiment of a compound of formula I having the structuralformula

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvateor ester thereof, wherein

W is —O—;

X is —N(R⁵)—;

U is a —(C(R⁵)(R⁷))—;

R¹, R² and R⁵ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;

R³ and R⁴ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl, arylalkyl and —CN;

R⁶ and R⁷ are independently selected from the group consisting of H,aryl, heteroaryl, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryalkyl and arylalkyl;

R⁸ is independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R¹⁰ is independently selected from the group consisting of H, alkyl,alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and—N(R¹⁵)(R¹⁶);

R¹⁵, R¹⁵ and R¹⁷ are independently selected from the group consisting ofH, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R¹⁸-alkyl,R¹⁸-cycloalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkyl,R¹⁸-heterocycloalkylalkyl, R¹⁸-aryl, R¹⁸-arylalkyl, R¹⁸-heteroaryl andR¹⁸-heteroarylalkyl; or

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO₂,halo, heteroaryl, HO-alkyoxyalkyl, —CF₃, —CN, alkyl-CN, —C(O)R¹⁹,—C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂, —C(O)NH₂—C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR¹⁹, —S(O)₂R²⁰,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁰, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R²⁰, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons can be linked together to form

R¹⁹ is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R²⁰ is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl,heteroaryl or heteroarylalkyl;

and wherein each of the alkyl, aryl, heteroaryl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl, andheteroarylalkyl groups in R¹, R²R³, R⁴, R⁵, R⁶ and R⁷ are independentlyunsubstituted or substituted by 1 to 5 R²¹ groups independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR¹⁵,—C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, ═NOR¹⁵, —N₃, —NO₂ and —S(O)₂R¹⁵; and wherein each of thealkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²¹ are independently unsubstituted orsubstituted by 1 to 5 R²² groups independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl,heteroaryl, halo, —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,-alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,═NOR¹⁵, —NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons can be linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together can be a C₂ to C₄ chain wherein, optionally, one, twoor three ring carbons can be replaced by —C(O)— or —N(H)— and R¹⁵ andR¹⁶, together with the atoms to which they are attached, form a 5 to 7membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkenyl and alkynyl groups in R²³ are independently unsubstituted orsubstituted by 1 to 5 R²⁷ groups independently selected from the groupconsisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,halo, —CF₃, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴,C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)₂C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, R²⁷-alkyl, R²⁷-cycloalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkyl, R²⁷-heterocycloalkylalkyl, R²⁷-aryl,R²⁷-arylalkyl, R²⁷-heteroaryl and R²⁷-heteroarylalkyl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, aryl, arylalkyl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R²⁹ is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl.

Another embodiment of the invention is a process for preparing acompound of Formula B:

the process comprising the steps of:

(a) reacting the compound of Formula A:

with R³—X in a solvent in the presence of a base, optionally with ZnCl₂,and a palladium/phosphine catalyst at about −78 to 0° C., wherein X isCl, Br, I, or OTf;

(b) raising the temperature of the reaction mixture to about 50-100° C.;and

(c) treating with an acid, to provide the compound of Formula B, wherein

W is —C(O)— or —S(O)₂—;

R¹ is selected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, aryl and heteroaryl;

R³ is selected from the group consisting of aryl, heteroaryl andalkenyl; and

R⁶ and R⁷ are selected from the group consisting of H, aryl, heteroaryl,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl and heteroarylalkyl.

In another embodiment of the process to prepare the compound of FormulaB the solvent is an ether (e.g. THF, diethyl ether), hydrocarbon (e.g.toluene), amide (e.g. DMF) or sulfoxide (e.g. DMSO).

In another embodiment of the process to prepare the compound of FormulaB, the palladium/phosphine catalyst is Pd₂(dba)₃, PdCl₂,PdOAc₂/Davephos,1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-phos),Bis(2-diphenylphosphinophenyl)ether,9,9-Dimethyl-4,5-bis(diphenylphoshino)xanthene,2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl,1,1′-Bis(diphenylphosphino)ferrocene, 1,4-Bis(diphenylphosphino)butane,1-dicyclohexylphosphino-2-di-tert-butylphosphinoethylferrocene(CyPF-tBu), Bis(2-diphenylphosphinophenyl)ether (DPEphos),9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) or1,1′-Bis(diphenylphosphino)ferrocene (DPPF), triphenylphosphine,1,3-bis(diphenylphospino)propane, 1,2-bis(diphenylphosphino)ethane,1,4-bis(diphenylphosphino)butane, tri-tertbutylphosphine,tricyclohexylphosphine, 1,1′-bis(di-tert-butylphosphino)ferrocene,1,1′-bis(di-isopropylphosphino)ferrocene, tri-o-tolylphosphine,1,1′-bis(diphenylphosphino)ferrocene, di-tert-butylphenylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, FibreCat (e.g. FibrecatAnchored Homogenous Catalysts, FibreCat 1001, 1007, 1026, 1032 fromJohnson Matthey Catalysts) or2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos).

In another embodiment of the process to prepare the compound of FormulaB, the acid is selected from the group consisting of trifluoroaceticacid, hydrochloric acid and hydrobromic acid.

In another embodiment of the process to prepare the compound of FormulaB, X is bromide.

In another embodiment of the process to prepare the compound of FormulaB, the base is selected from the group consisting of LIHMDS, LDA, BuLi,s-BuLi and tert-Butyllithium.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one cholinesterase inhibitor,acetyl- and/or butyrylchlolinesterase inhibitors can be used. Examplesof cholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred. Preferably, thesecombinations are directed to the treatment of Alzheimer's disease.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one muscarinic m₁ agonist or m₂antagonist can be used. Examples of m₁ agonists are known in the art.Examples of m₂ antagonists are also known in the art; in particular, m₂antagonists are disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352;5,889,006; 6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138;6,294,554; 6,043,255; and 6,458,812; and in WO 03/031412, all of whichare incorporated herein by reference.

In other aspects of the invention relating to a combination of at leastone compound of formula I and at least one other agent, for example abeta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoAreductase inhibitor such as atorvastatin, lovastatin, simvistatin,pravastatin, fluvastatin and rosuvastatin; cholesterol absorptioninhibitors such as ezetimibe; non-steroidal anti-inflammatory agentssuch as, but not necessarily limited to ibuprofen, relafen or naproxen;N-methyl-D-aspartate receptor antagonists such as memantine;anti-amyloid antibodies including humanized monoclonal antibodies;vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptorinverse agonists or CB1 receptor antagonists; antibiotics such asdoxycycline; growth hormone secretagogues; histamine H3 antagonists;AMPA agonists; PDE4 inhibitors; GABA_(A) inverse agonists; inhibitors ofamyloid aggregation; glycogen synthase kinase beta inhibitors; promotersof alpha secretase activity. Preferably, these combinations are directedto the treatment of Alzheimer's disease.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with acholinesterase inhibitor to treat cognitive disorders, these two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising a compound of formula I anda cholinesterase inhibitor in a pharmaceutically acceptable carrier canbe administered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the cholinesteraseinhibitor can be determined from published material, and may range from0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda cholinesterase inhibitor are to be administered, they can be providedin a kit comprising in a single package, one container comprising acompound of formula I in a pharmaceutically acceptable carrier, and aseparate container comprising a cholinesterase inhibitor in apharmaceutically acceptable carrier, with the compound of formula I andthe cholinesterase inhibitor being present in amounts such that thecombination is therapeutically effective. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


2. A compound, or a stereolsomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


3. A compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereolsomer, ortautomer, having the formula:


4. A compound, or a stereolsomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


5. A compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


6. A compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


7. A compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, having the formula:


8. A pharmaceutical composition comprising at least one compound of anyone of claims 1, 2, 3 - 7, or a stereolsomer or tautomer thereof, or apharmaceutically acceptable salt of said compound, stereoisomer, ortautomer, and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition according to claim 8, further comprising at least oneadditional pharmaceutically active agent.
 10. A pharmaceuticalcomposition according to claim 9, wherein said at least one additionalactive agent is selected from a cholinesterase inhibitor, a muscarinicm₁ agonist, and a muscarinic m₂ antagonist.
 11. A pharmaceuticalcomposition according to claim 10, wherein said at least one additionalactive agent is selected from a cholinesterase inhibitor.
 12. Apharmaceutical composition according to claim 10, wherein said at leastone additional active agent is selected from a muscarinic m₁ agonist anda muscarinic m₂ antagonist.